JP2011515487A - Bicyclic nitroimidazoles covalently linked to substituted phenyloxazolidinones - Google Patents

Abstract

  The present invention relates to a series of bicyclic nitroimidazole-substituted phenyloxazolidinones in which the bicyclic nitroimidazole pharmacophore is covalently linked to phenyloxazolidinone, pharmaceutical compositions thereof, and prevention and treatment of bacterial infections A method of using the composition to do so is provided. Phenyloxazolidinones substituted with bicyclic nitroimidazoles possess surprising antibacterial activity against wild-type and resistant strains of pathogens and are therefore caused by several of these pathogens such as Mycobacterium tuberculosis Useful for prevention, control and treatment of human and veterinary bacterial infections.

Description

  This application is entitled “Phenyloxazolidinone Substituted with Bicyclic Nitroimidazole (Biciclic Nitroimidazole-Substituted Phenyl Oxidolinones), filed Mar. 26, 2008, the entire contents of which are incorporated herein by reference. No. 61 / 070,855, the priority of US Provisional Patent Application No. 61 / 070,855.

  The present invention relates to phenyloxazolidinones substituted with bicyclic nitroimidazoles in which the bicyclic nitroimidazole pharmacophore is chemically bonded to the phenyloxazolidinone pharmacophore via a covalent bond.

  The disturbing increase in bacterial resistance to existing antibacterial agents is a major clinical challenge. Accordingly, there is a need in the art for compounds, compositions, and methods for treating warm-blooded animals suffering from bacterial infections and resistant to conventional antibacterial treatments. The occurrence of multidrug resistant tuberculosis ("MDRTB") is a serious public threat. Tuberculosis (“TB”) is highly infectious. Corrosive pathogenic Mycobacterium tuberculosis bacteria spread easily from person to person in the droplets formed when a person suffering from active TB sneezes or coughs. MDRTB is very difficult to treat and the majority of patients do not respond to conventional treatment. The total treatment cost of an individual suffering from MDRTB may be 10 times the conventional treatment cost, and the therapeutic drug cost may be 21 times alone. The preferred treatment for classic TB consists of isoniazid, rifampin, pyrazinamide and ethambutol, combining four drugs in the first two months of intense treatment, followed by two drug cocktails of rifampin and isoniazid for four months Used in the second treatment phase. MDRTB patients require specialized treatment with additional medications that can include streptomycin and ciprofloxacin for almost two years.

Bicyclic nitroimidazoles are known antibacterial agents, which are powerful agents against Mycobacterium tuberculosis bacteria. A series of nitroimidazo [2,1-b] oxazole derivatives have been reported to exhibit antibacterial properties including antitubercular activity (Nagarajan, K. 1989). The compound of formula (a) where R is ethyl (ie 2-ethyl-5-nitro-2,3-dihydro [2,1-b] imidazo-oxazole, also known as CGI17341) is Have been shown to exhibit activity (Ashtekar, D. 1993). More recently, 2,3-dihydro-6-nitroimidazo (2,1-b) oxazole (WO2005 / 042542 A1 and Sasaki, H.2006) represented by formula (b) is an agent for treating tuberculosis Wherein R ₁ represents H, alkyl, and the like, and R ₂ is alkoxy, aryloxy, and the like. Another class of bicyclic nitroimidazoles are nitro- [2,1-b] imidazopyran compounds, which have been reported to exhibit antibacterial properties including antitubercular activity (US Pat. No. 6,087,358), represented by formula (c), wherein R ₁ and R ₂ are various alkyloxy or aryloxy substituents, X is O, S, NR _2, etc. , Y, Z are CH ₂ , CHR ₂ and a heteroatom.

  Oxazolidinones are a new class of synthetic antimicrobial agents that kill Gram-positive pathogens by inhibiting the early stages of protein synthesis. Oxazolidinone inhibits the formation of ribosome initiation complexes, including 30S and 50S ribosomes, resulting in prevention of initiation complex formation. Due to their novel mechanism of action, these compounds are active against pathogens that are resistant to other clinically prescribed antibiotics. WO2006043121 discloses piperazinylphenyloxazolidinones substituted with heteroaryl, US Pat. No. 5,736,545 describes azolylpiperazinylphenyloxazolidinones and US Pat. No. 5,880. , 118 discloses substituted oxazine and thiazine oxazolidinone antibacterial agents. US Pat. No. 6,968,962 discloses phenyloxazolidinones having a C—C bond with a 4-8 membered heterocycle. US Pat. No. 5,981,528 discloses antibiotic oxazolidinone derivatives.

  Other previous publications in the field of oxazolidinones are US Pat. Nos. 4,801,600, 4,921,869, EPA 0352781 (January 31, 1989) and EPA 0316594 (May 24, 1989). is there.

  Oxazolidinones and bicyclic nitroimidazoles are known, but phenyloxazolidinone is covalently linked to the pharmacophore of bicyclic nitroimidazoles and the resulting bicyclic nitroimidazole substituted phenyloxazolidinones are aerobic and anaerobic. There are no references disclosing their use as antibacterial agents against gram-positive and gram-negative bacteria, particularly mycobacteria and clostridial.

  The present invention relates to phenyloxazolidinones substituted with bicyclic nitroimidazoles that exhibit a surprising synergistic effect against Mycobacterium tuberculosis under anaerobic growth conditions.

  The hybrid compounds of the present invention are dual-function antibacterial agents that act as both oxazolidinones and nitroimidazoles without in vivo biotransformation. The present invention also relates to methods for preparing phenyloxazolidinones substituted with pharmacologically active bicyclic nitroimidazoles and various intermediates used in the methods. The phenyloxazolidinone substituted with a bicyclic nitroimidazole of the present invention is a staphylococcus, such as Staphylococcus aureus, enterococci, such as Faecalis, streptococci, such as pneumococci, hemophilus, such as Haemophilus, Moraxella. E.g., cataract, and Escherichia, e.g., E. coli, mycobacteria, e.g., tuberculosis, Helicobacter, e.g., H. pylori, Clostridium, e.g., Sea difficile, Bacteroides, e.g. Vulgates), several human and veterinary aerobic and anaerobic species, including intercellular microorganisms such as Chlamydia and Rickettsia, and Mycoplasma, such as Mycoplasma pneumoniae It is useful as an effective antimicrobial agent against ram-positive and gram-negative pathogens. Phenyloxazolidinones substituted with bicyclic nitroimidazoles of the present invention exhibit surprising activity against anaerobic organisms, and thus include infections of the genus Mycobacterium, Clostridium, Cryptosporidium or Helicobacter, It can be used as an effective drug for the treatment of pathogenic infections. The present invention also relates to pharmaceutical compositions containing phenyloxazolidinones substituted with bicyclic nitroimidazoles and methods for treating and preventing bacterial infections using such compositions.

  In an embodiment of that principle, the present invention provides a series of bicyclic nitroimidazole substituted phenyloxazolidinones represented by general formula I, or a pharmaceutically acceptable salt thereof:

Wherein R ₁ is hydrogen, (C ₁ -C ₆ ) alkyl, aryl, heteroaryl, or heterocycloalkyl, n is 0, 1, or 2, and X ₁ and X ₂ are Independently, H, CF ₃ , Cl, OCF ₃ or F, G is —OH, substituted or unsubstituted triazole, heteroaryl or —NHCOR ₂ , and R ₂ is (C ₁ -C ₆ ) Alkyl, cycloalkyl, aryl, or heteroaryl, and L is a linker, or a linker group selected from one or a combination of 2 to 5 of the following groups:
1) (C ₁ -C ₆ ) alkylene,
_{2) (C} 3 ~C ₈₎ cycloalkylene,
3) Arylene,
4) Heteroarylene,
5) heterocycloalkylene containing 1 to 3 heteroatoms,
6) -C (= O)-,
7) -O-,
8) -S (O) _n- , wherein n is a number of 0, 1, or 2.
_{9) -N (R 3) -} ,
10) -C (R ₄ ) = C (R ₅ )-
[Wherein the carbon or nitrogen atom of the linker group is optionally substituted with 1 to 3 substituents, R ₃ , R ₄ and R ₅ are hydrogen, (C ₁ -C ₆ ) alkyl, Aryl, heteroaryl, or heterocycloalkyl, R ₄ and R ₅ can be joined together to form a bond]].

  Another aspect of the present invention is to provide a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient.

  One other aspect of the present invention provides a method of treating a microbial infection in a mammal comprising administering to the mammal a pharmaceutical composition containing a pharmaceutically effective amount of a compound of formula (I). Is to provide.

Shows a general method for synthesizing phenyloxazolidinones substituted with a bicyclic nitroimidazole of formula (I) having either 1,3 or 1,4-substituted arylene or heteroarylene in the linking group “L”. FIG. Diagram showing another general method for synthesizing phenyloxazolidinones substituted with a bicyclic nitroimidazole of formula (I) having various linker groups "L" and having a pharmacophore of bicyclic nitroimidazoxazole It is. Synthesis of phenyloxazolidinones substituted with a bicyclic nitroimidazole of formula (I) having various arylene or heteroarylene groups in the linker “L” and having a pharmacophore of bicyclic nitroimidazoxazole It is a figure which shows the general method of. Synthesize phenyloxazolidinones substituted with a bicyclic nitroimidazole of formula (I) having various alkylene, alkenylene or alkynylene groups in the linker "L" and having a pharmacophore of bicyclic nitroimidazoxazole It is a figure which shows another general method. It is a figure which shows the scheme which synthesize | combines 2- (4-bromo-phenyl) -2-methyl-oxirane. 1 is a diagram showing a scheme for synthesizing 2- (4-bromo-phenyl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole. FIG. 3- [2-Fluoro-4 ′-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -biphenyl-4-yl] -5-hydroxy It is a figure which shows the scheme which synthesize | combines methyl- oxazolidin-2-one. N- {3- [2-fluoro-4 '-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -biphenyl-4-yl]- FIG. 2 shows a scheme for synthesizing 2-oxo-oxazolidine-5-ylmethyl} -acetamide. It is a figure which shows the scheme which synthesize | combines 5-bromo- 2-isopropenyl- pyridine. It is a figure which shows the scheme which synthesize | combines 5-bromo- 2- (2-methyl- oxiranyl) -pyridine. FIG. 2 shows a scheme for synthesizing 2- (5-bromo-pyridin-2-yl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole. N- (3- {3-Fluoro-4- [6- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -pyridin-3-yl FIG. 1 shows a scheme for synthesizing] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. 1- [4- (5-Bromo-pyrimidin-2-yl) -piperazin-1-yl] -3- (2-chloro-4-nitro-imidazol-1-yl) -2-methyl-propan-2- It is a figure which shows the scheme which synthesize | combines all. 2- [4- (5-Bromo-pyrimidin-2-yl) -piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole is synthesized It is a figure which shows a scheme. N- [3- (3-Fluoro-4- {2- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -piperazine- FIG. 1 shows a scheme for synthesizing 1-yl] -pyrimidin-5-yl} -phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide. Di-tert-butyl phosphate 3- {3-fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 FIG. 1 shows a scheme for synthesizing (Iloxy) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl ester. Phosphoric acid mono- (3- {3-fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy)- FIG. 2 shows a scheme for synthesizing (pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) ester. 3- [3-Fluoro-4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yl) -phenyl] -5-hydroxymethyl- It is a figure which shows the scheme which synthesize | combines oxazolidin-2-one. N- {3- [3-Fluoro-4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yl) -phenyl] -2- FIG. 2 shows a scheme for synthesizing oxo-oxazolidine-5-ylmethyl} -acetamide. It is a figure which shows the scheme which synthesize | combines 2-allyl-2- (4-bromo-phenyl) -6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole. N- {3- [4 '-(2-allyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -2-fluoro-biphenyl-4-yl]- FIG. 2 shows a scheme for synthesizing 2-oxo-oxazolidine-5-ylmethyl} -acetamide. Synthesis of 3- [4- (2-allyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -phenyl] -5-hydroxymethyl-oxazolidin-2-one It is a figure which shows the scheme to do.

  Terms and phrases used herein have meanings and definitions known in the art. Some of the more commonly used phrases are described in more detail below.

The carbon atom content of the various hydrocarbon-containing moieties is indicated by a prefix that specifies the minimum and maximum number of carbon atoms in the moiety, ie, the prefix C _i -C _j is an integer “i” to an integer “j”. The number of carbon atoms (including both ends) is shown. Thus, for example, C ₁ -C ₆ alkyl refers to alkyl of ₁ to ₆ (inclusive) carbon atoms.

  As used herein, the term “alkyl” refers to a monovalent group of a saturated linear or branched hydrocarbon group. Examples of alkyl groups include methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, neo-pentyl, and n-hexyl. The alkyl groups of the present invention are optionally substituted. Preferred alkyl groups of the present invention have 1 to 6 carbons.

  As used herein, the term “alkenyl” refers to a monovalent group of an unsaturated straight or branched hydrocarbon group having at least one C═C double bond. Examples of alkenyl groups include allyl or propenyl, butenyl, isobutenyl, pentenyl and the like. The alkenyl groups of the present invention are optionally substituted.

  As used herein, the term “alkynyl” refers to a monovalent group of an unsaturated straight or branched hydrocarbon group having at least one C≡C triple bond. Examples of alkynyl groups include propargyl, butynyl, isobutynyl, pentynyl and the like. The alkynyl groups of the present invention are optionally substituted.

  As used herein, the terms “alkylene”, “alkenylene” or “alkynylene” refer to a divalent group of an alkyl, alkenyl, or alkynyl group as defined above. Examples of alkylene groups include methylene, ethylene, propylene, iso-propylene, n-butylene, isobutylene, n-hexylene and the like. Examples of alkenylene groups include ethenylene, propenylene and the like. Examples of alkynylene groups include ethynylene, propynylene and the like. The “alkylene”, “alkenylene” or “alkynylene” groups of the present invention are optionally substituted.

As used herein, the term “alkylamino” refers to an amino group (—NH ₂ ) in which one hydrogen atom is replaced by an alkyl group. Examples of alkylamino include methylamino, ethylamino, propylamino, and isopropylamino.

  The term “alkylthio” as used herein refers to an alkyl group, as defined herein, attached to a sulfur atom. Examples of alkylthio include methylthio, ethylthio, propylthio, and isopropylthio.

  As used herein, the term “alkoxy” refers to an alkyl group as previously defined attached to an oxygen atom. Examples of alkoxy include methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, tert-butoxy, neo-pentoxy and n-hexyloxy. The alkoxy groups of the present invention are optionally substituted.

  As used herein, the term “aryl” refers to a monovalent group of carbocyclic aromatic groups, including phenyl, naphthyl, and anthracenyl. The aryl groups of the present invention are optionally substituted.

  As used herein, the term “arylene” refers to an optionally substituted divalent group of an aryl group as defined above, such as phenylene.

  As used herein, the term “cycloalkyl” refers to a monovalent group of a saturated carbocyclic group having 3-8 carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Say. The cycloalkyl groups of the present invention are optionally substituted.

  As used herein, the term “cycloalkylene” refers to a divalent group of saturated carbocyclic groups having from 3 to 8 carbons. The cycloalkylene groups of the present invention are optionally substituted.

  As used herein, the term “halogen” or “halide” refers to fluorine, chlorine, bromine and iodine atoms, and the term “halo” refers to —F, —Cl, —Br, And -I.

  As used herein, the term “heteroaryl” refers to 5 or 6 ring atoms, wherein at least one ring atom is selected from the group consisting of oxygen, sulfur, and nitrogen, with the remaining ring atoms being carbon. A cyclic aromatic group having Heteroaryl groups of the present invention include furan, imidazole, isothiazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinoline, thiazole, 1,3,4-thiadiazole, triazole, and tetrazole. Includes what is induced. The heteroaryl groups of the present invention are optionally substituted.

  As used herein, the term “heteroarylene” refers to 5 or 6 ring atoms, wherein at least one ring atom is selected from the group consisting of oxygen, sulfur, and nitrogen, with the remaining ring atoms being carbon. A divalent cyclic aromatic group having Heteroarylene groups are optionally substituted.

  As used herein, the term “heteroatom” refers to an oxygen, nitrogen or sulfur atom.

As used herein, the term “heterocycloalkyl” refers to a non-aromatic 5, 6 or 7 membered ring having one or more heteroatoms independently selected from oxygen, sulfur and nitrogen, or It refers to a bicyclic or tricyclic group, where each 5-membered ring has 0-1 double bonds and each 6-membered ring has 0-2 double bonds. The nitrogen and sulfur heteroatoms are optionally oxidized, the nitrogen heteroatoms can optionally be quaternized, and any of the above heterocycles can be an aryl or heteroaryl ring and Can be condensed. Exemplary heterocycloalkyl include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, morpholinyl, isothiazolidinyl, and tetrahydrofuran Nil is included. Heterocycloalkyl groups of the present invention, _{optionally, -F, -Cl, -OH, -NO} 2, -CN, -C (O) - alkyl, -C (O) - aryl, -C (O) - heteroaryl, -CO ₂ - alkyl, -CO ₂ - aryl, -CO ₂ - _{heteroaryl, -C (O) NH 2,} -C (O) NH- alkyl, -C (O) NH- aryl, - C (O) NH- heteroaryl, -OC (O) - alkyl, -OC (O) - aryl, -OC (O) - _{heteroaryl, -OC (O) NH 2,} -OC (O) NH- alkyl , -OC (O) NH- aryl, -OCONH- heteroaryl, -NHC (O) - alkyl, -NHC (O) - aryl, -NHC (O) - heteroaryl, -NHCO ₂ - alkyl, -NHCO ₂ - aryl, -NHCO _{2 Heteroaryl, -NHC (O) NH 2,} -NHC (O) NH- alkyl, -NHC (O) NH- aryl, -NHC (O) NH- heteroaryl, -SO ₂ - alkyl, -SO ₂ - aryl , -SO ₂ - _{heteroaryl, -SO 2 NH 2, -SO 2} NH- alkyl, _-SO 2 NH- aryl, _-SO 2 NH- heteroaryl, - alkyl, - cycloalkyl, - cycloheteroalkyl, -CF _{3, -CH 2 OH, -CH 2} NH 2, - aryl, - heteroaryl, - benzyl, - benzyloxy, - aryloxy, - heteroaryloxy, - alkoxy, - methoxymethoxy, - methoxyethoxy, - amino, -Benzylamino, -arylamino, -heteroarylamino, -alkylamino, -thio, -ary Substituted with 1, 2, or 3 substituents independently selected from ruthio, -heteroarylthio, -benzylthio, -alkylthio, or -methylthiomethyl.

  As used herein, the term “heterocycloalkylene” refers to a divalent heterocycloalkyl group as defined above. The heterocycloalkylene groups of the present invention can be optionally substituted.

  As used herein, the term “hydroxyl” refers to —OH.

  The terms “optional”, “optionally” or “optionally substituted” may be followed by the event or situation described, but not necessarily, but the event or situation occurs It means that cases and cases that do not occur are included. For example, “an aryl group optionally substituted with 1 to 3 substituents” means that a substituent may be present, but not necessarily present, and the description includes aryl Included are situations where the group is mono-, di- or tri-substituted with a substituent and situations where the aryl group is not substituted with a substituent.

As used herein, the term “substituent” refers to —F, —Cl, —OH, —NO ₂ , —CN, —C (O) -alkyl, —C (O) -aryl, —C ( O) - heteroaryl, -CO ₂ - alkyl, -CO ₂ - aryl, -CO ₂ - _{heteroaryl, -C (O) NH 2,} -C (O) NH- alkyl, -C (O) NH- aryl , -C (O) NH- heteroaryl, -OC (O) - alkyl, -OC (O) - aryl, -OC (O) - _{heteroaryl, -OC (O) NH 2,} -OC (O) NH - alkyl, -OC (O) NH- aryl, -OCONH- heteroaryl, -NHC (O) - alkyl, -NHC (O) - aryl, -NHC (O) - heteroaryl, -NHCO ₂ - alkyl, - NHCO ₂ - aryl, -NHCO ₂ - Haitai _{Aryl, -NHC (O) NH 2,} -NHC (O) NH- alkyl, -NHC (O) NH- aryl, -NHC (O) NH- heteroaryl, -SO ₂ - alkyl, -SO ₂ - aryl, -SO ₂ - _{heteroaryl, -SO 2 NH 2, -SO 2} NH- alkyl, _-SO 2 NH- aryl, _-SO 2 NH- heteroaryl, - alkyl, - cycloalkyl, - heterocycloalkyl, -CF _{3 , -CH 2 OH, -CH 2 NH} 2, - aryl, - heteroaryl, - benzyl, - benzyloxy, - aryloxy, - heteroaryloxy, - alkoxy, - methoxymethoxy, - methoxyethoxy, - amino, - Benzylamino, -arylamino, -heteroarylamino, -alkylamino, -thio, -arylthio , -Heteroarylthio, -benzylthio, -alkylthio, or -methylthiomethyl.

  As used herein, the term “substituted” refers to the covalent attachment of one or more substituents.

  Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images are termed “enantiomers”. Where the compound has an asymmetric center, for example when the carbon atom is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric centers, explained by Cahn and Prelog's R- and S-rank rules, or the manner in which molecules rotate the plane of polarization, and dextrorotatory Or named levorotatory (ie, (+) or (−)-isomer, respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing an equal proportion of enantiomers is called a “racemic mixture”. The compounds of the present invention may have one or more asymmetric centers and therefore such compounds may be produced as individual (R)-or (S) -stereoisomers or as mixtures thereof. Can do. Unless otherwise indicated, the description or nomenclature for a particular compound in this specification and in the claims is intended to include both the individual enantiomers and their racemic or other mixtures.

  A “pharmaceutically acceptable carrier, diluent or excipient” is generally safe, non-toxic and useful for the preparation of a pharmaceutical composition that is not biologically or otherwise undesirable. And any carrier that is acceptable for veterinary use and for pharmacological use in humans. As used herein and in the claims, “pharmaceutically acceptable carrier” includes both one and more than one such carrier.

  “Pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, Lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2 .2] Oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4′-methylenebis- (3-hydroxy 2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and other organic acids Acid addition salts, etc., or acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth ions, or aluminum ions, or ethanolamine, diethanolamine, triethanol Examples include salts formed when coordinated with organic bases such as amines, tromethamine, and N-methylglucamine.

  “Treating” a disease or “treatment” includes preventing a disease, ie, a mammal that may have been exposed to or predisposed to a disease but has not yet experienced or indicated symptoms of the disease. In animals, preventing clinical symptoms of the disease from occurring, inhibiting the disease, ie, stopping or reducing the occurrence of the disease or its clinical symptoms, or reducing the disease, ie, the disease or its Includes causing regression of clinical symptoms.

  “Therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. “Therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

  “Leaving group” has the meaning conventionally associated with it in synthetic organic chemistry, ie, an atom or group that can be displaced by a nucleophile and is halogen, alkylsulfonyloxy, ester, or amino For example, chloro, bromo, iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy, methoxy, N, O-dimethylhydroxyl-amino and the like.

  The compounds of the invention are generally named according to the IUPAC or CAS scientific name system. Abbreviations well known to those skilled in the art may be used (eg, “Ph” is phenyl, “Me” is methyl, “Et” is ethyl, “h” is time, “rt” is room temperature).

  In an embodiment of that principle, the present invention provides a series of nitroimidazole substituted phenyloxazolidinones represented by general formula I, or a pharmaceutically acceptable salt thereof:

Wherein R ₁ is hydrogen, (C ₁ -C ₆ ) alkyl, aryl, heteroaryl, or heterocycloalkyl, n is 0, 1, or 2, and X ₁ and X ₂ are Independently, H, CF ₃ , Cl, OCF ₃ or F, G is —OH, substituted or unsubstituted triazole, heteroaryl or —NHCOR ₂ , and R ₂ is (C ₁ -C ₆ ) Alkyl, cycloalkyl, aryl, or heteroaryl, and L is a linker, or a linker group selected from one or a combination of 2 to 5 of the following groups:
1) (C ₁ -C ₆ ) alkylene,
_{2) (C} 3 ~C ₈₎ cycloalkylene,
3) Arylene,
4) Heteroarylene,
5) heterocycloalkylene containing 1 to 3 heteroatoms,
6) -C (= O)-,
7) -O-,
8) -S (O) _n- , wherein n is a number of 0, 1, or 2.
_{9) -N (R 3) -} ,
_{10) -C (R 4) =} C (R 5) -,
[Wherein the carbon or nitrogen atom of the linker group is optionally substituted with 1 to 3 substituents, R ₃ , R ₄ and R ₅ are hydrogen, (C ₁ -C ₆ ) alkyl, Aryl, heteroaryl, or heterocycloalkyl, R ₄ and R ₅ can be joined together to form a bond]].

  Preferred compounds of the invention of formula (I) are those wherein L is a bond or a group selected from one or a combination of 2 to 3 of the following structural elements:

In which R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are independently optionally substituted H, hydroxyl, amino, alkyl, alkylamino, alkoxy, aryl, heteroaryl, and R ₁₃ together with the nitroimidazole ring,

And m and n are independently the number 0, 1 or 2, and Z is O, S, CR ₁₄ R ₁₅ [wherein R ₁₄ And R ₁₅ are independently H, alkyl, aryl or heteroaryl groups], G is hydroxyl, —NHCOCH ₃ , triazole.

  More preferred compounds of the invention are those represented by general formula II, or pharmaceutically acceptable salts thereof:

Wherein A _{1 to} A ₆ are independently selected from a bond, heteroatom, or optionally substituted or unsubstituted carbon with a substituent, and L ₁ and L ₂ are independently , Join,

And G is —OH, substituted or unsubstituted triazole, or —NHCOCH ₃ , where A ₁ -A ₆ are not more than two consecutive heteroatoms].

The most preferred group of compounds is (S, S) -N- {3- [3-fluoro-4- (4- {2- [4- (2-nitro-6,7-dihydro-5H-imidazo [2 , 1-b] [1,3] oxazin-6-yloxymethyl) -phenoxy] -acetyl} -piperazin-1-yl) -phenyl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide; , S) -N- (3- {3-Fluoro-4- [4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yl (Oxymethyl) -benzyloxy] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -N- (3- {3-fluoro-4- [3- (2-nitro- 6,7-Dihydro-5H-imidazo [2,1-b] 1,3] oxazin-6-yloxymethyl) -benzyloxy] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -N- (3- {3-fluoro-4 -[5- (2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl) -pyridin-2-yloxy] -phenyl} -2 -Oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -N- (3- {3-fluoro-4- [4- (2-nitro-6,7-dihydro-5H-imidazo [2, 1-b] [1,3] oxazin-6-yloxymethyl) -phenoxy] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -N- [3- (3 -Fluoro 4- {1- [4- (2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl) -benzyl] -1H- [1 , 2,3] triazol-4-ylmethoxy} -phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide; (S, S) -N- (3- {3-fluoro-4- [6- ( 2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5 Ylmethyl) -acetamide; (S, S) -N- (3- {3-fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,1 3] Oxazin-6-yloxy) -pyrimidine-5 Yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -N- (3- {3-fluoro-4- [2- (2-nitro-6,7-dihydro) -5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyridin-4-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; N- (3 -{3-Fluoro-4- [5- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -pyridin-3-yl] -phenyl} 2-oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -N- (3- {3-fluoro-4- [5- (2-nitro-6,7-dihydro-5H-imidazo [ 2,1-b] [1, ] Oxazin-6-yloxymethyl) -pyridin-2-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -N- (3- {3-fluoro-4 -[6- (2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl) -pyridin-3-yl] -phenyl} -2 -Oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -N- (3- {3-fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2, 1-b] [1,3] oxazin-6-yloxy) -pyridazin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -N- (3- {3-Fluoro-4 [4-morpholin-4-yl-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyrimidin-5-yl] -Phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -N- (3- {3-fluoro-4- [4-methoxy-2- (2-nitro-6,7) (Dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; , S) -N- (3- {4- [4-Dimethylamino-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 Yloxy) -pyrimidin-5-yl] -3 -Fluoro-phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -5- {4- [5- (acetylamino-methyl) -2-oxo-oxazolidine-3-yl] 2-fluoro-phenyl} -2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -nicotinic acid methyl ester; , S) -5- {4- [5- (acetylamino-methyl) -2-oxo-oxazolidine-3-yl] -2-fluoro-phenyl} -2- (2-nitro-6,7-dihydro- 5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -nicotinic acid; (S, S) -N- (3- {3-fluoro-4- [4- (2-nitro -6,7-dihydro-5H-imida [2,1-b] [1,3] oxazin-6-yloxy) -pyrimidin-2-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -N- (3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyrimidine-4- Yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -N- (3- {3-fluoro-4- [5-methyl-6- (2-nitro-6) , 7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -N- 3- {3-Fluoro-4- [2-methyl-6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyridine -3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; N- (3- {3-fluoro-4- [5- (2-methyl-6-nitro-2,3- (S, S) -N- (3) dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -pyridin-2-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; -{3-Fluoro-4- [4- (4-methoxy-benzyloxy) -2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine- 6-yloxy) -pyrimidine-5 -Yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -N- (3- {3-fluoro-4- [2- (2-nitro-6,7- Dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -6-oxo-1,6-dihydro-pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine- 5-ylmethyl) -acetamide; (S, S) -N- (3- {3-fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [ 1,3] oxazin-6-yloxy) -4-trifluoromethyl-pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -N- {3 -[2,6-difluoro 4 ′-(2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl) -biphenyl-4-yl] -2-oxo-oxazolidine -5-ylmethyl} -acetamide; N- {3- [4- (6-nitro-imidazo [2,1-b] -2 (3H) -8-aza-spiro [4.5] des-8-yl ) -3-Fluorophenyl] -2-oxo-oxazolidine-5 (S) -ylmethyl} -acetamide; (S, R) -3- [2-fluoro-4 ′-(2-nitro-6,7-dihydro) -5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl) -biphenyl-4-yl] -5-hydroxymethyl-oxazolidin-2-one; (S, R) -3 -{3-Fluoro-4- [2- (2-nitro- 6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyrimidin-5-yl] -phenyl} -5-hydroxymethyl-oxazolidine-2-one; S, R) -3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy)- Pyridin-3-yl] -phenyl} -5-hydroxymethyl-oxazolidin-2-one; (S, S) -N- {3- [2-fluoro-4 ′-(2-nitro-6,7-dihydro) -5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl) -biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide; (S, S) -N- [3- (3-Fluoro-4 -{4- [2- (2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -acetyl] -piperazin-1-yl}- Phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide; N- (3- {3-fluoro-4- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2, 1-b] oxazol-2-ylmethyl) -piperazin-1-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; (S, R) -3- [2-fluoro-4′- (2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl) -biphen-4-yl] -5- [1,2,3 ] Triazol-1-ylmethyl-o Xazolidin-2-one; (S, R) -3- {3-fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxymethyl) -pyridin-3-yl] -phenyl} -5- [1,2,3] triazol-1-ylmethyl-oxazolidine-2-one; N- {3- [2-fluoro- 4 '-(2-Methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -Acetamide; N- {3- [2-fluoro-3 '-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -biphenyl-4- Il] -2-oxo-Oki Zolidin-5-ylmethyl} -acetamide; N- {3- [2′-chloro-2-fluoro-4 ′-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] Oxazol-2-ylmethoxy) -biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide; N- {3- [3′-chloro-2-fluoro-4 ′-(2-methyl-) 6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide; N- {3- [3′-cyano-2-fluoro-4 ′-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -biphenyl-4-yl]- 2 -Oxo-oxazolidin-5-ylmethyl} -acetamide; N- (3- {2-fluoro-4 '-[(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole) -2-ylmethyl) -amino] -biphenyl-4-yl}-
2-oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -N- (3- {3-fluoro-4- [3- (2-nitro-6,7-dihydro-5H-imidazo [2 , 1-b] [1,3] oxazin-6-yloxy) -propenyl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; (E) -N- (3- {3-fluoro- 4- [2- (2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -yloxy) -vinyl] -phenyl} -2-oxo -Oxazolidine-5 (S) -ylmethyl) -acetamide; N- (3- {3-fluoro-4- [1- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [ 1,3] Oxazine-6 (S) -Iluo (Cimethyl) -vinyl] -phenyl} -2-oxo-oxazolidine-5 (S) -ylmethyl) -acetamide; N- (3- {3-fluoro-4- [2- (2-nitro-6,7-dihydro) -5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -acetyl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; N- (3- {3- Fluoro-4- [1-hydroxy-1-hydroxymethyl-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -ethyl ] -Phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -N- (3- {3-fluoro-4- [3- (2-nitro-6,7-dihydro-) 5H-I Dazo [2,1-b] [1,3] oxazin-6-yloxy) -prop-1-ynyl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide; (S, S) -N -{3- [2,2'-difluoro-5 '-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl)- Biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide; (S, S) -N- {3- [2-fluoro-3 ′-(2-nitro-6,7-dihydro-) 5H-imidazo [2,1-b] [1,3] oxazin-6-loxymethyl) -biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide; and N- {3- [3-Fluoro-4- (2-methyl Tyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -phenyl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide, and pharmaceutically acceptable salts thereof Its salt.

  The phenyloxazolidinones substituted with the bicyclic nitroimidazoles of the present invention can be prepared by following the general synthetic scheme.

Scheme 1 shown in FIG. 1 is a phenyl substituted with a bicyclic nitroimidazole of formula (I) having either a 1,3 or 1,4-substituted arylene or heteroarylene in the linking group “L”. A general method for synthesizing oxazolidinone (IA) is illustrated. A bicyclic nitroimidazole, such as nitroimidazoline (1a), similarly prepared by following the synthesis disclosed in US Pat. No. 6,087,358, is prepared in an organic solvent such as DMF, such as sodium hydride. Any of 1,3 or 1,4-substituted aryl or heteroaryl compound (1b) in the temperature range of −80 ° C. to 80 ° C. in the presence of a base [wherein A ₁ , A ₂ , A ₃ and A ₄ is selected from a bond, N, O or a carbon with an optional substituent attached, X ₁₁ is Cl, Br or I, X ₁₂ is a leaving group, and m is 0 or The ether compound (1c) is obtained. An ether compound (1c) is prepared from a phenyloxazolidinone boronate compound (1d) (prepared as described by US Pat. No. 7,129,259 or WO 2004/078753) and a biaryl coupling (or Suzuki or palladium catalyst). Action) under conditions, for example, in the presence of a catalyst such as palladium tetrakistriphenylphosphine (Pd (Ph ₃ P) ₄ ) and a base such as potassium carbonate in an organic or aqueous organic solvent such as THF or DMF and water. Coupling at a temperature of ˜110 ° C. produces phenyloxazolidinone (IA) substituted with a bicyclic nitroimidazole of the present invention.

Alternate synthesis of bicyclic nitroimidazole-substituted phenyl oxazolidinone (IA) is the compound (1a), 1, 3 or 1,4-substituted aryl or heteroaryl boronic acid ester having a leaving group X ₁₂ By substitution reaction with any of compound (1e) to obtain ether compound (1f). The reaction is carried out in the same manner as in the conversion of compound (1a) to ether compound (1c). Boronic ester compound (1f) is optionally prepared from ether compound (1c) and diboronic ester (1 g) under palladium catalyst (or Suzuki) coupling conditions similar to those described above. The resulting compound (1f) is coupled under similar Suzuki conditions with a halo-substituted phenyloxazolidinone (1h) (prepared as described by WO 2006/038100) to give the bicyclic nitro of the present invention. Phenyloxazolidinone (IA) substituted with imidazole is produced.

Scheme 2 shows another general synthesis of phenyloxazolidinones substituted with a bicyclic nitroimidazole of formula (I) having various linker groups “L” and having a pharmacophore of bicyclic nitroimidazoxazole. The method is illustrated. A phenyloxazolidinone substituted with a bicyclic nitroimidazole of formula (IB) having an arylene or heteroarylene linker group is prepared from the nitroimidazole epoxide (2a). The synthesis of nitroimidazole epoxide (2a) has been disclosed (Sasaki, H. 2006). Ring opening of the epoxide, followed by ring closure, is a 1,3 or 1,4-substituted aryl or heteroaryl compound (2b) with a nucleophile X _{14 wherein} X ₁₄ is O, NH or S. ), And in the presence or absence of a base such as sodium hydride in an organic solvent such as DMF or ethanol at a temperature range of −80 ° C. to 100 ° C. A nitroimidazooxazole derivative compound (2c) is produced. When X ₁₄ is NH, the reaction is optionally carried out in the presence of a copper salt such as cuprous bromide. Coupling the phenyloxazolidinone boronate derivative (2d) under Suzuki conditions as before yields compound (IB). A phenyloxazolidinone substituted with a bicyclic nitroimidazole of formula (IC) having a piperazine group in the linker “L” is also prepared from the nitroimidazole epoxide (2a). The synthesis of phenyloxazolidinone piperazine (2e) is known in the art (US Pat. No. 5,547,950 or Brickner, 1996). The ring opening of epoxide using phenyloxazolidinone piperazine is affected by the temperature range from room temperature to 100 ° C. in the presence or absence of a base such as sodium acetate in ethanol or the like. The resulting amino alcohol (2f) is treated with a base such as sodium hydride in an organic solvent such as DMF to yield compound (IC). A phenyloxazolidinone substituted with a bicyclic nitroimidazole of formula (ID) having an ether or sulfide linker group is a nitroimidazole epoxide (2a) and a nucleophile X _{15 wherein} X ₁₅ is O, NH , Or S] is prepared from phenyloxazolidinone (2 g) (prepared as described by US Publication No. US 2007/0155714). The preparation can be carried out in a solvent such as DMF in the presence or absence of a base such as sodium hydride, or as described (Sasaki, H. et al .: Journal of Medicinal Chemistry (2006), 49 (26), 7854-7860).

Substituted with a bicyclic nitroimidazole of formula (I) having various arylene or heteroarylene groups in the linker “L” shown in FIG. 3 and having a pharmacophore of bicyclic nitroimidazoxazole. Still another general method for synthesizing phenyloxazolidinone is illustrated. A phenyloxazolidinone substituted with a bicyclic nitroimidazole of formula (IE) having an arylene or heteroarylene linker group and a heteroatom X ₁₅ as defined above is phenyloxazolidinone (3a) (US2007 / From (prepared in the same way as described by US Pat. The aryl substitution with the leaving group X ₁₁ and carboxaldehyde or a compound having an electron attractive group G ₂ such as ester (3b), the coupling product (3c) is obtained. The reaction is carried out in a solvent such as DMF or DMSO, in the presence of a base such as potassium carbonate or cesium carbonate, in the presence or absence of a phase transfer catalyst such as tetrabutylammonium bromide, in a temperature range from room temperature to 200 ° C. To do. The carboxaldehyde or ester group G _2, using a reducing agent such as sodium borohydride, is converted to the alcohol in a solvent such as ethanol, followed by reduction product (3c), such as methanesulfonate or halide further converted to a compound having a leaving group _{X 16} (3d). Coupling of compound (3d) with bicyclic nitroimidazole (1a) is performed as before to give phenyloxazolidinone substituted with a bicyclic nitroimidazole of formula (IE). The phenyloxazolidinone substituted with a bicyclic nitroimidazole of formula (IF) of the present invention is prepared by reacting propargyl bromide with compound (3a). Substitution of bromide gave compound (3e) which reacted with azide-substituted bicyclic nitroimidazole (3f) in the presence of a copper catalyst such as copper sulfate in a linker group “L”. A phenyloxazolidinone substituted with a bicyclic nitroimidazole of the formula (IF) having a triazole at the end is obtained.

Scheme 4, shown in FIG. 4, substituted with a bicyclic nitroimidazole of formula (I) having various alkylene, alkenylene or alkynylene groups in the linker “L” and having a pharmacophore of bicyclic nitroimidazoxazole Yet another general method for synthesizing the synthesized phenyloxazolidinones is illustrated. Compound (1a) is alkylated with an allyl halide or other compound (4a) having a leaving group X ₁₇ to give compound (4b), which is obtained by using a base such as sodium hydride in a solvent such as DMF. In the presence, it is carried out at a temperature between room temperature and 80 ° C. Compound (4b) is coupled with phenyloxazolidinone boronate (1d) under the same palladium catalysis conditions as defined above (or Suzuki) and replaced with a bicyclic nitroimidazole of formula (IH) The resulting phenyl oxazolidinone is obtained. Similar reaction sequences using various substituted allyl halides and the like produce phenyloxazolidinone compounds substituted with bicyclic nitroimidazoles of formula (IJ) and (IK) of the present invention of formula (I).

  The above synthetic scheme is a preferred scheme for synthesizing phenyloxazolidinones substituted with bicyclic nitroimidazoles. It will be apparent to those skilled in the art that other reaction sequences and alternative reagents can be used for the same family name. These alternatives are also within the scope of the present invention.

  Preferred compounds of the present invention are optically pure diastereoisomers having (S) or (R) -configuration in either the linker “L” or both the pharmacophore of phenyloxazolidinone and nitroimidazole. Ma. It is known in the art that one diastereomer is more active than the other. However, racemic mixtures are also useful, although larger amounts of racemic material may be required to produce the same effect as pure diastereomers.

  If desired, the pure diastereomeric mixture is resolved by means known to those skilled in the art. A single pure material can be obtained by resolution of the diastereomeric mixture by HPLC. Alternatively, resolution of the racemic mixture can be achieved by selective crystallization of the salt form using methods known to those skilled in the art.

  A compound of formula (I), or a prodrug or pharmaceutically acceptable salt or solvate thereof, can be administered as a neat compound or as a pharmaceutical composition containing a compound of the invention.

  The pharmaceutical compositions of the present invention may be prepared using standard and conventional techniques to convert a compound of formula (I) into a solid or liquid pharmaceutically acceptable carrier and optionally pharmaceutically acceptable adjuvants and excipients. It can be prepared by mixing with. Solid form compositions include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can be at least one substance that can also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic material, low melting wax, cocoa butter, and the like. Liquid form compositions include solutions, suspensions, and emulsions. For example, the compounds of the present invention can be dissolved in water, water-propylene glycol, or water-polyethylene glycol and optionally contain suitable conventional colorants, flavors, stabilizers and thickeners. . The phenyloxazolidinone substituted with a bicyclic nitroimidazole of formula (I) of the present invention may be used alone or in combination with other antibacterial and / or non-antibacterial agents, as is known to those skilled in the art. Can be used.

  Humans and other mammals such as cattle, horses, sheep, pigs, dogs, and cats can be treated with the present invention. The present invention can be administered in a manner and dosage form similar to the known antibacterial agents described above. For therapeutic use to treat or combat bacterial infections in humans and warm-blooded animals, the compound of formula (I), or a pharmaceutical composition thereof, is administered orally in conventional techniques, for example in solid and liquid dosage forms. And / or parenterally (IV, IM, SC) to reach a certain concentration, ie the amount or blood level of the active ingredient in the animal being treated, antibacterial effective or appropriate. Administered in unit dosage form to maintain

  Generally, the amount of compound (I) in the pharmaceutical composition is about 0.5% to about 90% by weight. The antibacterial effective dose of Compound (I) is about 0.1 to about 100 mg / kg body weight / day, more preferably about 3 to about 50 mg / kg body weight / day. The amount of phenyloxazolidinone substituted with a bicyclic nitroimidazole of formula (I) in the pharmaceutical composition, its exact unit dosage form, frequency of administration, and route of administration all vary and treat infections Specific mode of administration, specific compound used, efficacy of specific compound, desired concentration, patient age, weight, gender, and overall health status and requirements, nature of bacterial infection being treated, well-known to the physician And widely adjustable depending on several factors known to those skilled in the art, including severity and the like. Also, depending on the situation, the initial dose administered can be increased above the upper limit to quickly achieve the desired blood level, or the initial dose can be less than optimal and treatment It should be understood that the daily dose can be progressively increased during the course of this. Conventional pharmaceutical forms suitable for parenteral (mixtures, suspensions in oil) and oral (tablets, capsules, syrups, suspensions, etc.) are known to those skilled in the art.

  The compounds of the present invention can be administered by any suitable route, for example, oral, topical, buccal, inhalation, sublingual, rectal, vaginal, transurethral, nasal, topical, transdermal, ie transdermal, or parenteral. Administration can be by administration (including intravenous, intramuscular, subcutaneous, and intracoronary). Parenteral administration can be accomplished using a needle and syringe or by infusion with IV fluids such as 5% dextrose or normal saline.

  When a compound or pharmaceutical composition of the invention is administered parenterally, i.e. by injection, e.g. by intravenous injection, or by other parenteral routes of administration, this is generally a pharmaceutically acceptable amount, e.g. Formula (I) dissolved in a pharmaceutically acceptable liquid carrier such as water for injection, and a buffer to provide a suitable buffered isotonic solution, such as one having a pH of about 3.5 to about 10. ) As a soluble salt (acid addition salt or base salt) of the compound.

  Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+)-lysine, and L (+)-arginine. The compound of formula (I) is generally dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 1 to about 400 mg per ml of solution. The resulting liquid pharmaceutical composition is administered so as to obtain an antibacterial effective dose as described above.

  For human use, the compound of formula (I) can be administered alone, but is generally mixed with a pharmaceutical carrier selected in view of the intended route of administration and standard pharmaceutical practice. To administer. A pharmaceutical composition for use in accordance with the present invention comprises one or more excipients and adjuvants that facilitate the processing of a compound of formula (I) into a pharmaceutically usable preparation. It can be formulated in a conventional manner using a physiologically acceptable carrier.

  These pharmaceutical compositions can be manufactured in a conventional manner, for example, by conventional mixing, dissolving, granulating, dragee making, wet grinding, emulsifying, encapsulating, encapsulating, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen. When a therapeutically effective amount of a compound of the present invention is administered orally, the composition is typically in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition can further contain a solid carrier such as gelatin or an adjuvant. Tablets, capsules, and powders contain about 5 to about 95% of a compound of the invention, preferably about 25 to about 90% of a compound of the invention. When administered in liquid form, liquid carriers such as water, petroleum, or oils of animal or vegetable origin can be added. The liquid form of the composition can further contain saline, dextrose or other sugar solution, or glycol. When administered in liquid form, the composition contains from about 0.5 to about 90% by weight of a compound of the invention, preferably from about 1 to about 50% of a compound of the invention.

  For oral administration, the compounds of the formula (I) can be readily formulated by combining them with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the present invention to be formulated as tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, etc., for ingestion by the patient being treated. . Pharmaceutical preparations for oral use include a mixture of granules after adding solid excipients to the compound of formula (I), optionally crushing the resulting mixture and, if desired, adding appropriate adjuvants Can be obtained by processing a tablet to obtain a tablet or dragee core. Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added.

  For administration by inhalation, the compounds of the invention can be delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer, using a suitable propellant. In the case of a pressurized aerosol, the unit dose can be determined by providing a valve that delivers a metered amount. For example, gelatin capsules and cartridges for use in an inhaler or insufflator can be formulated to contain a suitable powder-based powder mixture of the compound and lactose or starch.

  The compounds can be formulated for parenteral administration by injection, eg, by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, eg, in ampoules or multiple dose containers, with preservatives. The composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and also contains compounding agents such as suspending, stabilizing, and / or dispersing agents. Can do.

  Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In addition, suspensions of the active compounds can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound to allow for the preparation of highly concentrated solutions. Alternatively, the compositions of the invention can be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, prior to use.

  The compounds of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, eg containing conventional suppository bases. In addition to the formulations already described, the compounds can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compound may be formulated using a suitable polymer or hydrophobic material (eg, as an acceptable emulsion in oil) or ion exchange resin, or as a slightly less soluble derivative, eg, a slightly less soluble salt. Can do.

  For topical administration, the compounds of the present invention can be applied in neat form, for example when the compound is a liquid. However, it is desirable to administer the compound to the skin as a composition in combination with a dermatologically acceptable carrier that can be a solid, semi-solid, or liquid. Useful solid carriers include, but are not limited to, finely divided solids such as talc, clay, crystalline cellulose, silica, alumina and the like. Useful liquid carriers include, but are not limited to, water, alcohols, glycols, and water-alcohols, which can optionally dissolve or disperse the compounds of the present invention at effective levels with the aid of surfactants. / Glycol mixture. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resulting liquid composition can be applied topically by an absorbent pad used to impregnate bandages and other bandages, or sprayed onto the affected area using a pump-type or aerosol sprayer.

  For veterinary use, the compound of formula (I) or its non-toxic sale is administered as a suitably acceptable formulation in accordance with normal veterinary practice. The veterinarian can readily determine the dosing regimen and route of administration that is most appropriate for a particular animal.

General Methods and Definitions All starting materials used in these examples are either purchased from commercial suppliers or prepared according to published procedures. Reagents are purchased from commercial suppliers and used without further purification. All temperatures are in degrees Celsius. When solvent pairs are used, the ratio of solvents used is volume / volume (v / v). When using a solid solution in a solvent, the ratio of solid to solvent is weight / volume (wt / v). The reaction using a water-sensitive reagent is performed in a nitrogen atmosphere. Concentration of the solution or removal of the solvent is performed by reduced pressure (under vacuum) rotary evaporation. Flash chromatography is performed using silica gel 60 as normal phase adsorbent or C18 silica gel as reverse phase adsorbent. Thin layer chromatography (“TLC”) Performed using pre-coated plates purchased from Merck, the spots are visualized using long wave ultraviolet light followed by an appropriate staining reagent. Preparative thin layer chromatography (TLC) is performed using EM silica gel (SG) 60 F ₂₅₄ plates (20 × 20 cm, thickness 2 mm) and the bands are visualized using a long wave ultraviolet lamp. Nuclear magnetic resonance (“NMR”) spectra are recorded on a Varian 400 MHz magnetic resonance spectrometer. ¹ H NMR refers to proton nuclear magnetic resonance spectroscopy, and the chemical shift is in ppm from tetramethylsilane to the lower magnetic field side, or the residual solvent signal (CHCl ₃ = δ 7.27, CH ₃ OD = δ 3.31). ) As an internal standard. ¹ H NMR information is tabulated in the following manner: number of protons, multiplicity (s, singlet; d, doublet; t, triplet; q, quadruple; m, multiplet; td, two The triplet of the double line; dt, the double line of the triple line), and the coupling constant (J) are shown in hertz. The prefix app is sometimes applied when the true signal multiplicity is not resolved, and the prefix br indicates a broad signal. Electrospray ionization mass spectra are recorded on a Finnegan LCQ advantage spectrometer and reported as M + H or M + Na, referring to protonated molecular ions or their sodium complexes.

Abbreviations Abbreviations used herein have the meaning known by those skilled in the art. Specifically, Ac represents an acetyl group, BOC represents a t-butoxycarbonyl group, Bn represents a benzyl group, Bu represents a butyl group, Bz represents a benzoyl group, Cbz represents a benzyloxycarbonyl group. DCM represents dichloromethane, DMAP represents 4-N, N-dimethylaminopyridine, DMF represents N, N-dimethylformamide, DMSO represents dimethyl sulfoxide, Et represents an ethyl group, EtOAc represents acetic acid Represents ethyl, Me represents a methyl group, Ph represents a phenyl group, Pr represents a propyl group, TEA represents triethylamine, TFA represents trifluoroacetic acid, THF represents tetrahydrofuran, TMS represents a trimethylsilyl group, is there. The following abbreviations are also used: mmol (mmol), milliliter (mL), milligram (mg), microliter (uL), microgram (ug).

The following examples describe how to prepare various compounds and / or how to perform various processes of the present invention and should be construed as merely illustrative. In no way should it be construed as a limitation on the foregoing disclosure. Those skilled in the art will recognize appropriate variations of the procedure, both in terms of reagents and reaction conditions and techniques.
Example 1

  (S, S) -N- {3- [3-Fluoro-4- (4- {2- [4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1 , 3] oxazin-6-yloxymethyl) -phenoxy] -acetyl} -piperazin-1-yl) -phenyl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide:

Step 1. (4-Hydroxymethyl-phenoxy) -acetic acid tert-butyl ester. A suspension of 4-hydroxymethylphenol (3.70 g, 30 mmol), bromoacetic acid tert-butyl ester (6.0 mL, 40 mmol), K ₂ CO ₃ (16.6 g, 120 mmol) in acetonitrile (100 mL) was added. Stir at 60 ° C. for 16 h under N ₂ . The reaction mixture was filtered and the solvent removed under reduced pressure to give the crude product, which was purified by flash chromatography using EtOAc / hexanes to give the title product as an oil (6. 22g, 87%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.29 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 4.62 (d, J = 5. 6 Hz, 2H), 4.52 (s, 2H), 1.49 (s, 9H).

Step 2. (4-Chloromethyl-phenoxy) -acetic acid tert-butyl ester. To a stirred solution of (4-hydroxymethyl-phenoxy) -acetic acid tert-butyl ester (2.38 g, 10 mmol) in methylene chloride (50 mL) was added triethylamine (3.5 mL, 25 mmol) at 0 ° C. under N _2. Addition was followed by MsCl (1.20 mL, 15 mmol). The mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours. The resulting mixture was diluted with methylene chloride and washed with water, 5% K ₂ CO ₃ solution and saturated brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give the title product as an oil (2.40 g, 94%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 4.56 (s, 2H), 4 .51 (s, 2H), 1.48 (s, 9H).

Step 3. (S)-[4- (2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxylmethyl) -phenoxy] -acetic acid tert-butyl ester . 2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -ol (148 mg, 0.80 mmol) in anhydrous DMF (8.0 mL) and To a stirred solution of (4-chloromethyl-phenoxy) -acetic acid tert-butyl ester (300 mg, 1.0 mmol) was added 60% NaH (50 mg, 1.3 mmol) at −60 ° C. under N ₂ . The resulting mixture was slowly warmed to room temperature and stirred at room temperature for 1.5 hours. The mixture was diluted with EtOAc, washed with water, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by preparative TLC plate (5% MeOH in dichloromethane) to give the title product (142 mg, 44%). ESI MS m / z 406 (M + H ⁺ ), 428 (M + Na ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (s, 1H), 7.23 (d, J = 8.4 Hz, 2H) 6.87 (d, J = 8.4 Hz, 2H), 4.67 to 4.53 (m, 3H), 4.52 (s, 2H), 4.31 (d, J = 11.6 Hz, 1H), 4.15 to 4.06 (m, 3H), 1.49 (s, 9H).

Step 4. (S) -N- {3- [3-Fluoro-4- (4- {2- [4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 ] Oxazin-6-yloxymethyl) -phenoxy] -acetyl} -piperazin-1-yl) -phenyl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide. [4- (2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -yloxylmethyl in TFA / CH ₂ Cl ₂ (2 mL) ) -Phenoxy] -acetic acid tert-butyl ester (100 mg, 0.25 mmol) was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo, diluted with DCM, and this solution was added to N- [3- (3-fluoro-4-piperazin-1-yl-phenyl) -2-oxo-oxazolidine-5-ylmethyl] Acetamide (50 mg, 0.15 mmol) (prepared by following the procedure disclosed by US Pat. No. 5,547,950 or Brickner, 1996), HOBt (21.6 mg, 0.16 mmol), EDCI (30. 7 mg, 0.16 mmol) and DIPEA (0.20 ml) were added. The mixture was stirred at room temperature for 24 hours, diluted with DCM, washed with saturated NaHCO ₃ , 1N HCl and saturated NaHCO ₃ , dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by preparative TLC plate (5% MeOH in dichloromethane) to give the title product as a solid (6.0 mg, 4%). ESI MS m / z 668.4 (M + H ^< + ^> ).
Example 2

  (S, S) -N- (3- {3-Fluoro-4- [4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxymethyl) -benzyloxy] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1.6 (S)-(4-Chloromethyl-benzyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. Of 2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -ol (0.1 g, 0.54 mmol) in anhydrous DMF (1 mL). To the stirring solution was added NaH (60% dispersion in oil, 26.0 mg, 0.65 mmol) and stirred at 0 ° C. for 30 minutes. 1,4-Bis-chloromethyl-benzene (472 mg, 2.7 mmol) in anhydrous DMF (0.5 mL) was added to the reaction mixture, stirred at 0 ° C. for 30 minutes, and further stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was washed with hexanes to give the title compound as a solid (65 mg, 37%). ESI MS m / z 324 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.24 (m, 5H), 4.72 (d, J = 30.0 Hz, 1H), 4 .59 (m, 2H), 4.32 (d, J = 30.0 Hz, 1H), 4.16 (m, 1H), 1.60 (s, 4H).

Step 2. (S, S) -N- (3- {3-Fluoro-4- [4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxymethyl) -benzyloxy] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. 6 (S)-(4-Chloromethyl-benzyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine in acetonitrile (5.0 mL) ( 48 mg, 0.15 mmol), N- [3- (3-Fluoro-4-hydroxy-phenyl) -2-oxo-oxazolidine-5 (S) -ylmethyl] -acetamide (40 mg, 0.15 mmol) (US2007 / 0155714 A suspension of K ₂ CO ₃ (207 mg, 1.5 mmol) was stirred at 50 ° C. under nitrogen for 2 days. The reaction mixture was diluted with EtOAc, filtered and evaporated. The crude product was purified by preparative TLC plate (5% MeOH in dichloromethane) to give the title product as a solid (8.0 mg, 10%). ESI MS m / z 556.4 (M + H ⁺ ); ¹ H NMR (400 MHz, acetone) δ 7.67 (s, 1H), 7.51 (dd, J = 14.0, 2.8 Hz, 1H), 7.36 (d, J = 7.6 Hz, 2H), 7.28 (d, J = 7.6 Hz, 2H), 7.08 (d, J = 8.8 Hz, 1H), 7.04 (dd , J = 9.2, 2.8 Hz, 1H), 5.53 (s, 2H), 5.09 (d, J = 8.8 Hz, 1H), 4.70 to 4.63 (m, 3H) 4.45 (d, J = 11.6 Hz, 1H), 4.33 to 4.27 (m, 2H), 4.03 (t, J = 8.8 Hz, 1H), 3.71 (dd, J = 9.2, 6.8 Hz, 1H), 2.76 to 2.73 (m, 3H), 1.95 (s, 3H).
Example 3

  (S, S) -N- (3- {3-Fluoro-4- [3- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxymethyl) -benzyloxy] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1.6 (S)-(3-Chloromethyl-benzyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. The title compound follows the same procedure as described for the preparation of Example 2, except that 1,3-bis- (chloromethyl) -benzene was used instead of 1,4-bis- (chloromethyl) -benzene. Was prepared. ESI MS m / z 473 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (s, 1H), 7.32-7.19 (m, 4H), 4.71 (d, J = 30 Hz, 1H), 4.60 (d, J = 21 Hz, 2H), 4.33 (d, J = 30.0 Hz, 1H), 4.15 (m, 3H), 3.45 (s, 2H) ), 3.41 (s, 4H), 2.37 (s, 4H), 1.44 (s, 9H).

Step 2. (S, S) -N- (3- {3-Fluoro-4- [3- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxymethyl) -benzyloxy] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound is obtained by reacting the starting material 6- (3-chloromethyl-benzyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine with 6- (4- Chloromethyl-benzyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Described for the preparation of Example 2 except that it was used in place of oxazine Was prepared by following the same procedure. ESI MS m / z 556.4 (M + H).
Example 4

  (S, S) -N- (3- {3-Fluoro-4- [5- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxymethyl) -pyridin-2-yloxy] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1. N- {3- [3-Fluoro-4- (5-formyl-pyridin-2-yloxy) -phenyl] -2-oxo-oxazolidine-5 (S) -ylmethyl} -acetamide. 6-Fluoro-pyridine-3-carbaldehyde (125 mg, 1.0 mmol), N- [3- (3-Fluoro-4-hydroxy-phenyl) -2-oxo-oxazolidine-5 (S A suspension of) -ylmethyl] -acetamide (200 mg, 0.746 mmol), K ₂ CO ₃ (552 mg, 4.0 mmol) was stirred at 60 ° C. under nitrogen for 15 hours. The reaction mixture was diluted with EtOAc, filtered and evaporated. The crude product was purified by flash chromatography (1: 1 hexane / EtOAc, followed by 1% MeOH in EtOAc) to give the title product as an oil (235 mg, 84%). ESI MS m / z 374 (M + H ⁺ ); ¹ H NMR (400 MHz, CD ₃ OD) δ 9.97 (s, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.29 ( dd, J = 8.4, 2.4 Hz, 1H), 7.70 (dd, J = 12.0, 1.6 Hz, 1H), 7.33-7.20 (m, 3H), 4.80 ˜4.78 (m, 1H), 4.19 (t, J = 9.0 Hz, 1H), 3.85 (dd, J = 9.6, 6.4 Hz, 1H), 3.58 (d, J = 4.8 Hz, 2H), 1.97 (s, 3H).

Step 2. N- {3- [3-Fluoro-4- (5-hydroxymethyl-pyridin-2-yloxy) -phenyl] -2-oxo-oxazolidine-5 (S) -ylmethyl} -acetamide. N- {3- [3-Fluoro-4- (5-formyl-pyridin-2-yloxy) -phenyl] -2-oxo-oxazolidine-5 (S) -ylmethyl} -acetamide (230 mg in MeOH (25 mL) , 0.62 mmol), NaBH ₄ (70 mg, 1.86 mmol) was added at room temperature. The mixture was stirred at room temperature for 24 hours, quenched with 1N HCl (2 ml), diluted with EtOAc and washed with H ₂ O. The organic layer was dried and concentrated in vacuo to give the title product as a colorless oil (232 mg, 100%). ESI MS m / z (M + H ⁺ ) 376; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.03 (d, J = 2.4 Hz, 1H), 7.83 (dd, J = 8.8, 2 .4 Hz, 1 H), 7.67 (dd, J = 12.8, 2.4 Hz, 1 H), 7.30 (dd, J = 8.8, 2.4 Hz, 1 H), 7.25 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 4.80 to 4.78 (m, 1H), 4.57 (s, 2H), 4.18 ( t, J = 9.2 Hz, 1H), 3.84 (dd, J = 9.2, 6.8 Hz, 1H), 3.57 (d, J = 4.8 Hz, 1H), 1.97 (s) , 3H).

  Step 3. Methanesulfonic acid 6- {4- [5 (S)-(acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxy} -pyridin-3-ylmethyl ester. N- {3- [3-Fluoro-4- (5-hydroxymethyl-pyridin-2-yloxy) -phenyl] -2-oxo-oxazolidine-5 (S) -ylmethyl} -acetamide (10 mL) in dichloromethane (10 mL) To a solution of 250 mg, 0.67 mmol) and triethylamine (0.35 mL), methanesulfonyl chloride (0.10 mL, 1.34 mmol) was added at 0 ° C. under nitrogen. The mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours. The reaction mixture was poured into water, extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo to give a yellowish oil. This is used directly in the next step.

Step 4. (S, S) -N- (3- {3-Fluoro-4- [5- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxymethyl) -pyridin-2-yloxy] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. From 2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -ol (111 mg, 0.60 mmol) in DMF (10 mL) and step 3 Of methanesulfonic acid 6- {4- [5 (S)-(acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxy} -pyridin-3-ylmethyl ester NaH (30 mg, 0.72 mmol, 60% purity) was added at −60 ° C. under nitrogen. The mixture was slowly warmed to room temperature and stirred at room temperature for 4 hours. The reaction mixture is poured into water, extracted with EtOAc, dried over sodium sulfate, and concentrated in vacuo to give the crude product, which is flash chromatographed on silica eluting with 5% MeOH in dichloromethane. Purification by chromatography gave the title product as a pale yellowish solid (92 mg, 25% over two steps). ESI MS m / z 543.4 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 8.4) 2.4 Hz, 1H), 7.61 (dd, J = 12.4, 2.4 Hz, 1H), 7.39 (s, 1H), 7.20-7.17 (m, 2H), 6. 99 (d, J = 8.8 Hz, 1H), 6.08 (t, J = 6.0 Hz, 1H), 5.28 (s, 2H), 4.79 to 4.76 (m, 1H), 4.64 to 4.53 (m, 3H), 4.32 (d, J = 12.0 Hz, 1H), 4.19 to 4.10 (m, 2H), 4.04 (t, J = 9) .0Hz, 1H), 3.79-3.64 (m, 2H), 2.03 (s, 3H).
Example 5

  (S, S) -N- (3- {3-Fluoro-4- [4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxymethyl) -phenoxy] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1. N- {3- [3-Fluoro-4- (4-formyl-phenoxy) -phenyl] -2-oxo-oxazolidine-5 (S) -ylmethyl} -acetamide. 4-Fluoro-benzaldehyde (276 mg, 2.22 mmol), N- [3- (3-Fluoro-4-hydroxy-phenyl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide (300 mg in DMF (15 mL) , 1.11 mmol), and a suspension of K ₂ CO ₃ (828 mg, 6.0 mmol) were stirred at 90 ° C. under nitrogen for 20 hours. The reaction mixture was diluted with EtOAc, washed with water and concentrated in vacuo. The crude product was purified by flash chromatography (1: 1 hexane / EtOAc followed by EtOAc) to give the title product as an oil (325 mg, 79%). ESI MS m / z (M + H ⁺ ) 373; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.91 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.64 (d , J = 12.4 Hz, 1H), 7.26 (d, J = 1.6 Hz, 1H), 7.18 (d, J = 6.8 Hz, 1H), 7.00 (d, J = 7. 2 Hz, 2H), 6.25 (t, J = 5.8 Hz, 1H), 4.83 to 4.80 (m, 1H), 4.08 (t, J = 9.0 Hz, 1H), 3. 82 (t, J = 8.0 Hz, 1H), 3.75 to 3.62 (m, 2H), 2.04 (s, 3H).

Step 2. N- {3- [3-Fluoro-4- (4-hydroxymethyl-phenoxy) -phenyl] -2-oxo-oxazolidine-5 (S) -ylmethyl} -acetamide. The title compound is N- {3- [3-fluoro-4- (4-formyl-phenoxy) -phenyl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide and N- {3- [3-fluoro- Follow the same procedure as described for the preparation of Example 4 except that 4- (5-formyl-pyridin-2-yloxy) -phenyl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide was used. Prepared. ESI MS m / z 375 (M + H ^< + ^> ).

Step 3. N- {3- [4- (4-Chloromethyl-phenoxy) -3-fluoro-phenyl] -2-oxo-oxazolidine-5 (S) -ylmethyl} -acetamide. N- {3- [3-Fluoro-4- (4-hydroxymethyl-phenoxy) -phenyl] -2-oxo-oxazolidine-5 (S) -ylmethyl} -acetamide (250 mg, 0. 0) in dichloromethane (10 mL). 67 mmol) and triethylamine (0.35 mL) were added methanesulfonyl chloride (0.10 mL, 1.34 mmol) at 0 ° C. under nitrogen. The mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours. The reaction mixture is poured into water, extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo to give the crude product, which is purified by flash chromatography on silica eluting with EtOAc. To give the title compound as an oil (210 mg, 80%). ESI MS m / z 393 (M + H ^< + ^> ).

Step 4. N- (3- {3-Fluoro-4- [4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl)- Phenoxy] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound is N- {3- [4- (4-chloromethyl-phenoxy) -3-fluoro-phenyl] -2-oxo-oxazolidin-5-ylmethyl} -acetamide and methanesulfonic acid 6- {4- [ The preparation of Example 4 was described except that 5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxy} -pyridin-3-ylmethyl ester was used instead. Prepared by following the same procedure as ESI MS m / z 542.4 (M + H ^< + ^> ).
Example 6

  (S, S) -N- [3- (3-Fluoro-4- {1- [4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxymethyl) -benzyl] -1H- [1,2,3] triazol-4-ylmethoxy} -phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide.

Step 1. N- [3- (3-Fluoro-4-prop-2-ynyloxy-phenyl) -2-oxo-oxazolidine-5 (S) -ylmethyl] -acetamide. Propargyl bromide (97 mg, 0.82 mmol), N- [3- (3-fluoro-4-hydroxy-phenyl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide (183 mg, 0) in acetonitrile (15 mL) .68 mmol), and a suspension of K ₂ CO ₃ (500 mg) was stirred at 55 ° C. under nitrogen for 3 hours. The reaction mixture was diluted with EtOAc, washed with water and evaporated to give the title product as an oil (186 mg, 89%). This was used directly in the next step. ESI MS m / z 307 (M + H ^< + ^> ).

Step 2.6 (S)-(4-Azidomethyl-benzyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. 6 (S)-(4-Chloromethyl-benzyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine (650 mg, in acetonitrile (20 mL). 2.0 mmol) and NaN ₃ (780 mg, 12 mmol) were stirred at 75 ° C. for 24 hours. The reaction mixture was filtered and the solvent removed under reduced pressure to give the title product as a yellowish solid (0.65 g, 98%). ESI MS m / z 331 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37 (s, 1H), 7.33-7.32 (m, 4H), 4.74 (d, J = 12.0 Hz, 1H), 4.64 to 4.59 (m, 2H), 4.36 to 4.33 (m, 3H), 4.19 to 4.11 (m, 3H).

Step 3. (S, S) -N- [3- (3-Fluoro-4- {1- [4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxymethyl) -benzyl] -1H- [1,2,3] triazol-4-ylmethoxy} -phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide. N- [3- (3-Fluoro-4-prop-2-ynyloxy-phenyl) -2-oxo-oxazolidine-5 (S) -ylmethyl] -acetamide (76 mg, 0.25 mmol) in THF (8.0 mL) ) And 6 (S)-(4-azidomethyl-benzyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine (83 mg, 0.25 mmol) To the solution was added Cu (16 mg, 0.25 mmol), CuSO ₄ (0.10 mL, 0.25 N in water) and water (2.0 mL) under nitrogen. The reaction mixture was stirred at room temperature under nitrogen for 24 hours. The volatile solvent was removed under reduced pressure and the crude product was purified by preparative TLC (5% MeOH in dichloromethane) to give as a yellow solid (90 mg, 57%). ESI MS m / z 627.5 (M + H ^< + ^> ).
Example 7

  (S, S) -N- (3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxy) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1.6 (S)-(5-Bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. 2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -ol (463 mg, 2.5 mmol) and 5-bromo-2-in DMF To a solution of fluoro-pyridine (528 mg, 3.0 mmol), NaH (200 mg, 5.0 mmol) was added at −60 ° C. under nitrogen. The mixture was slowly warmed to room temperature and stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc, washed with brine and concentrated in vacuo. The crude product was recrystallized from MeOH / H ₂ O to give the title compound as a yellow solid (0.603 g, 70%). ESI MS m / z 341, 343 (bromine pattern, M + H ⁺ ).

Step 2. (S, S) -N- (3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxy) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. 6- (5-Bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] in DMF / H ₂ O (10 / 1.5.5 mL) [1,3] oxazine (150 mg, 0.44 mmol), N- {3- [3-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl ) -Phenyl] -2-oxo-oxazolidin-5-ylmethyl} -acetamide (166 mg, 0.44 mmol) (Chen, S. et al .: as described by US Pat. No. 7,129,259 or Gravestot et al., WO 2004/078753. Preparation), degassing a suspension of Pd (Ph ₃ P) ₄ (58 mg, 0.05 mmol) and K ₂ CO ₃ (121 mg, 0.88 mmol) did. The mixture was heated to 80 ° C. for 2.5 hours, diluted with EtOAc, washed with brine and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography (5% MeOH in EtOAc) to give the title product (143 mg, 63%). ESI MS m / z 513.4 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.57 (D, J = 12.8, 2.8 Hz, 1H), 7.45 (s, 1H), 7.39 (t, J = 8.6 Hz, 1H), 7.30 (dd, J = 8. 8.2.0 Hz, 1 H), 6.86 (d, J = 8.8 Hz, 1 H), 5.99 (t, J = 6.0 Hz, 1 H), 5.79 (brs, 1 H), 4. 86 to 4.81 (m, 2H), 4.54 (d, J = 10.8 Hz, 1H), 4.41 (d, J = 2.4 Hz, 2H), 4.11 to 4.06 (m , 1H), 3.83 (dd, J = 8.8, 6.8 Hz, 1H), 3.72 to 3.66 (m, 2H), 2.03 (s, 3H).
Example 8

  (S, S) -N- (3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxy) -pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1.6 (S)-(5-Bromo-pyrimidin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. The title compound was prepared by following the same procedure as described for the preparation of Example 7, except that 5-bromo-2-fluoro-pyrimidine was used in place of 5-bromo-2-fluoro-pyridine. ESI MS m / z 342, 344 (bromine, M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.59 (s, 2H), 7.44 (s, 1H), 5.60 (s, 1H ), 4.85 (d, J = 14.8 Hz, 1H), 4.55 (d, J = 12.0 Hz, 1H), 4.48 to 4.38 (m, 2H).

Step 2. (S, S) -N- (3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxy) -pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound is 6- (5-bromo-pyrimidin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine 6- (5- Bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Described for the preparation of Example 7 except that it was used in place of oxazine. Prepared by following the same procedure as ESI MS m / z 514.5 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 8.85 (s, 2H), 8.26 (t, J = 5.8 Hz, 1H), 8.06 ( s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.64 (dd, J = 12.0, 2.0 Hz, 1H), 7.44 (dd, J = 8.0) , 2.4 Hz, 1H), 5.73 (s, 1H), 4.78 to 4.69 (m, 3H), 4.47 (s, 2H), 4.16 (t, J = 9.2 Hz). , 1H), 3.76 (dd, J = 9.2, 6.4 Hz, 1H), 3.41 (t, J = 5.2 Hz, 2H), 1.81 (s, 3H).
Example 9

  (S, S) -N- (3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxy) -pyridin-4-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1.6 (S)-(4-Bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. The title compound was prepared by following the same procedure as described for the preparation of Example 7, except that 4-bromo-2-fluoro-pyridine was used in place of 5-bromo-2-fluoro-pyridine. ESI MS m / z 341, 343 (bromine isotope pattern: M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (d, J = 5.2 Hz, 1H), 7.43 (s, 1H), 7.14 (dd, J = 5.2, 1.2 Hz, 1H), 7.00 (d, J = 1.2 Hz, 1H), 5.72 (bs, 1H), 4.78 ( dt, J = 12.8, 2.6 Hz, 1H), 4.51 (d, J = 12.0 Hz, 1H), 4.42 to 4.35 (m, 2H).

Step 2. N- (3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyridine- 4-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound is 6- (4-bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine 6- (5- Bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Described for the preparation of Example 7 except that it was used in place of oxazine. Prepared by following the same procedure as ESI MS m / z 513.3 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.17 (d, J = 5.2 Hz, 1H), 7.57 (dd, J = 13.2) 2.0 Hz, 1H), 7.46 (d, J = 5.2 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.29 (dd, J = 9.2, 2) .8 Hz, 1 H), 7.17 (m, 1 H), 6.94 (s, 1 H), 6.07 (t, J = 5.2 Hz, 1 H), 5.78-5.79 (m, 1 H) ), 4.85 to 4.82 (m, 2H), 4.55 (d, J = 12.4 Hz, 1H), 4.40 (d, J = 2.4 Hz, 2H), 3.82 (dd , J = 8.8, 6.4 Hz, 1H), 3.72 to 3.63 (m, 2H), 2.03 (s, 3H).
Example 10

  N- (3- {3-Fluoro-4- [5- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -pyridin-3-yl ] -Phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide.

Step 1.2- (5-Bromo-pyridin-3-yloxymethyl) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole. 5-Bromo-pyridin-3-ol (0.87 g, 5.0 mmol) and 2-bromo-1- (2-methyl-oxiranylmethyl) -4-nitro-1H-imidazole (20 ml) in DMF (20 ml) To a solution of 1.305 g, 5.0 mmol), sodium hydride (0.28 g, 7.0 mmol, 60% in mineral oil) was added at 0 ° C. The mixture was stirred at 0 ° C. for 10 minutes and stirred at 50 ° C. for 2 hours. The resulting mixture was cooled, diluted with water and extracted with ethyl acetate. The combined extracts were dried, concentrated and the residue was purified by silica gel chromatography eluting with hexane / EtOAc to give the title product (260 mg, 15%) as a yellow oil. ESI MS m / z 355, 357 (bromine isotope pattern, M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19 (s, 1H), 8.00 (s, 1H), 7.57 (S, 1H), 7.36 (s, 1H), 4.47 (d, J = 10.4 Hz, 1H), 4.30 (d, J = 10.4, 1H), 4.14 (d , J = 10.4 Hz, 1H), 4.07 (d, J = 10.4 Hz, 1H), 1.80 (s, 3H).

Step 2. N- (3- {3-Fluoro-4- [5- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -pyridin-3-yl ] -Phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound (mixture of two diastereomers) is 2- (5-bromo-pyridin-3-yloxymethyl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b ] Oxazole was used in place of 6- (5-Bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine Prepared by following the same procedure as described for the preparation of Example 7. ESI MS m / z 527.3 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 8.21 (d, J = 2.8 Hz, 1H), 7.90 ( s, 1H), 7.67 (dd, J = 13.2, 2 Hz, 1H), 7.57 (t, J = 8.8 Hz, 2H), 7.42 (dd, J = 8.8, 2 .4 Hz, 1 H), 4.85 to 4.80 (m, 1 H), 4.61 to 4.49 (m, 2 H), 4.41 (d, J = 10.8 Hz, 1 H), 4.24 To 4.17 (m, 2H), 3.86 (dd, J = 9.2, 6.4 Hz, 1H), 3.57 (dd, J = 4.8 Hz, 1H), 1.96 (s, 3H), 1.78 (s, 3H).
Example 11

  (S, S) -N- (3- {3-Fluoro-4- [5- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxymethyl) -pyridin-2-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1. (6-Bromo-pyridin-3-yl) -methanol. The title compound is 6-bromo-pyridine-3-carbaldehyde converted to N- {3- [3-fluoro-4- (5-formyl-pyridin-2-yloxy) -phenyl] -2-oxo-oxazolidine-5 Prepared by following the same procedure as described for the preparation of Example 4 (Step 2) except that it was used instead of ylmethyl} -acetamide. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 4 .70 (s, 2H), 2.32 (s, 1H).

  Step 2. Methanesulfonic acid 6-bromo-pyridin-3-ylmethyl ester and 2-bromo-5-chloromethyl-pyridine. The title compound is (6-bromo-pyridin-3-yl) -methanol replaced with N- {3- [3-fluoro-4- (5-hydroxymethyl-pyridin-2-yloxy) -phenyl] -2-oxo- Prepared by following the same procedure as described for the preparation of Example 4 (Step 3) except that it was used instead of oxazolidine-5-ylmethyl} -acetamide.

Step 3.6 (S)-(6-Bromo-pyridin-3-ylmethoxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. The title compound was prepared by replacing the mixture of methanesulfonic acid 6-bromo-pyridin-3-ylmethyl ester and 2-bromo-5-chloromethyl-pyridine produced above with 5-bromo-2-fluoro-pyridine. Prepared by following the same procedure as described for the preparation of Example 7 except that it was used. ESI MS m / z 355, 357 (bromine isotope, M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 8.32 (d, J = 2.8 Hz, 1H), 8.01 (s, 1H) 7.66 (dd, J = 8.0, 2.0 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 4.64 to 4.60 (m, 3H), 4. 43 (d, J = 11.6 Hz, 1H), 4.22 to 4.17 (m, 3H).

Step 4. (S, S) -N- (3- {3-Fluoro-4- [5- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxymethyl) -pyridin-2-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound is 6- (6-bromo-pyridin-3-ylmethoxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine 6- (5- Bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Described for the preparation of Example 7 except that it was used in place of oxazine. Prepared by following the same procedure as ESI MS m / z 527.5 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 8.25 (t, J = 6.0 Hz, 1H), 8.03 ( s, 1H), 7.98 (t, J = 8.8 Hz, 1H), 7.81 (d, J = 8.0, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.59 (dd, J = 14.0, 2.4 Hz, 1H), 7.43 (dd, J = 8.8, 2.0 Hz, 1H), 4.75 to 4.67 (m, 3H) 4.46 (d, J = 11.6 Hz, 1H), 4.25 to 4.23 (m, 2H), 4.15 (t, J = 13.0 Hz, 1H), 3.77 (dd, J = 9.2, 6.8 Hz, 1H), 3.40-3.20 (m, 4H), 2.05 (s, 1.35H), 1.81 (s, 1.65H).
Example 12

  (S, S) -N- (3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxymethyl) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1. Methanesulfonic acid 5-bromo-pyridin-2-ylmethyl ester. The title compound is (5-bromo-pyridin-2-yl) -methanol replaced with N- {3- [3-fluoro-4- (5-hydroxymethyl-pyridin-2-yloxy) -phenyl] -2-oxo- Prepared by following the same procedure as described for the preparation of Example 4 (Step 3) except that it was used instead of oxazolidine-5-ylmethyl} -acetamide. ESI MS m / z 266 and 268 (bromine isotope pattern, M + H ⁺ ).

Step 2.6 (S)-(5-Bromo-pyridin-2-ylmethoxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. The title compound follows the same procedure as described for the preparation of Example 7, except that methanesulfonic acid 5-bromo-pyridin-2-ylmethyl ester was used instead of 5-bromo-2-fluoro-pyridine. It was prepared by. ESI MS m / z 355 and 357 (bromine isotope pattern, M + H ⁺ ).

Step 3. (S, S) -N- (3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxymethyl) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound is 6 (S)-(5-bromo-pyridin-2-ylmethoxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine 6 ( S)-(5-Bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Prepared by following the same procedure as described for the preparation of Example 7. ¹ H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 8.24 (t, J = 5.2 Hz, 1H), 8.01 (s, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 4.8, 2.8 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.43 (d, J = 8) 0.0 Hz, 1H), 7.40 (dd, J = 8.8, 2.4 Hz, 1H), 4.75 to 4.67 (m, 3H), 4.46 (d, J = 11.2 Hz, 1H), 4.32 to 4.29 (m, 2H), 4.21 (dd, J = 13.2, 3.6 Hz, 1H), 4.13 (t, J = 9.0 Hz, 1H), 3.74 (dd, J = 9.2, 6.4 Hz, 1H), 3.88 (t, J = 6.0 Hz, 1H), 3.40-3.20 (m, 3H), 1.80 (S, 3H).
Example 13

  (S, S) -N- (3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxy) -pyridazin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1.6 (S)-(6-Chloro-pyridazin-3-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. The title compound was prepared by following the same procedure as described for the preparation of Example 7, except that 3,6-dichloro-pyridazine was used instead of 5-bromo-2-fluoro-pyridine. ESI MS m / z 298 (M + H ^< + ^> ).

Step 2. (S, S) -N- (3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxy) -pyridazin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound is 6 (S)-(6-chloro-pyridazin-3-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine 6- (5-Bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Except for that used in place of oxazine Prepared by following the same procedure as described for preparation. ESI MS m / z 514.4 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 8.23 (bs, 1H), 8.05 (s, 1H), 7.97 (dd, J = 8. 8, 1.6 Hz, 1 H), 7.93 (d, J = 8.8 Hz, 1 H), 7.63 (dd, J = 14.0, 2.4 Hz, 1 H), 7.48 (dd, J = 8.8, 2.0 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 5.99 (s, 1H), 4.82 to 4.72 (m, 3H), 4 .51 (s, 1H), 4.17 (t, J = 9.0 Hz, 1H), 3.78 (dd, J = 9.2, 6.0 Hz, 1H), 3.41 (t, J = 5.2 Hz, 2H), 3.30-3.20 (m, 1H), 1.81 (s, 3H).
Example 14

  (S, S) -N- (3- {3-Fluoro-4- [4-morpholin-4-yl-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxy) -pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1.6 (S)-(5-Bromo-4-morpholin-4-yl-pyrimidin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1 , 3] Oxazine. The title compound was described for the preparation of Example 7 except that 4- (6-bromo-2-chloro-pyrimidin-4-yl) -morpholine was used instead of 5-bromo-2-fluoro-pyridine. Was prepared by following the same procedure. ESI MS m / z 427, 429 (bromine isotope, M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19 (s, 1H), 7.43 (s, 1H), 5.54 ( brs, 1H), 4.84 to 4.74 (m, 2H), 4.52 to 4.38 (m, 2H), 3.78 to 3.71 (m, 8H).

Step 2. (S, S) -N- (3- {3-Fluoro-4- [4-morpholin-4-yl-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxy) -pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound is 6 (S)-(5-Bromo-4-morpholin-4-yl-pyrimidin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [ 1,3] oxazine of 6 (S)-(5-bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine Prepared by following the same procedure as described for the preparation of Example 7, except that it was used instead. ESI MS m / z 599.5 (M + H ^< + ^> ).
Example 15

  (S, S) -N- (3- {3-Fluoro-4- [4-methoxy-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 ] Oxazin-6-yloxy) -pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidin-5-ylmethyl) -acetamide:

Step 1.6 (S)-(5-Bromo-4-methoxy-pyrimidin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine . The title compound was obtained by following the same procedure as described for the preparation of Example 7, except that 5-bromo-2-chloro-4-methoxy-pyrimidine was used instead of 5-bromo-2-fluoro-pyridine. Prepared. ESI MS m / z 372, 374 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (s, 1H), 7.43 (s, 1H), 5.61 (brs, 1H), 4.84 (dt, J = 12.4, 2.4 Hz, 1H), 4.53 (d, J = 11.6 Hz, 1H), 4.20 to 4.04 (m, 2H), 4.03 (S, 3H).

Step 2. (S, S) -N- (3- {3-Fluoro-4- [4-methoxy-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 ] Oxazin-6-yloxy) -pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound was 6- (5-bromo-4-methoxy-pyrimidin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine 6 Example 7 except that-(5-bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine was used. Prepared by following the same procedure as described for the preparation of ESI MS m / z 544.4 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 8.34 (s, 1H), 8.22 (t, J = 5.8 Hz, 1H), 8.05 ( s, 1H), 7.55 (dd, J = 12.8, 2.0 Hz, 1H), 7.42 (t, J = 8.4 Hz, 1H), 7.36 (dd, J = 8.8). , 2.0 Hz, 1H), 4.79 to 4.68 (m, 2H), 4.46 (s, 1H), 4.13 (t, J = 9.0 Hz, 1H), 3.87 (s) , 2H), 3.74 (dd, J = 9.2, 6.4 Hz, 1H), 3.40 (t, J = 5.4 Hz, 2H), 3.30-3.20 (m, 1H) 1.81 (s, 3H).
Example 16

  (S, S) -N- (3- {4- [4-Dimethylamino-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine- 6-yloxy) -pyrimidin-5-yl] -3-fluoro-phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1. [5-Bromo-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -yloxy) -pyrimidin-4-yl]- Dimethyl-amine. The title compound was as described for the preparation of Example 7, except that (5-bromo-2-chloropyrimidin-4-yl) -dimethyl-amine was used instead of 5-bromo-2-fluoro-pyridine. Prepared by following the same procedure. ESI MS m / z 385, 387 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 7.42 (s, 1H), 5.53 to 5.51 (m , 1H), 4.81 (dd, J = 12.8, 3.6 Hz, 1H), 4.50 (dd, J = 12.0, 2.0 Hz, 1H), 4.36 (d, J = 3.2 Hz, 2H), 3.24 (s, 6H).

Step 2. (S, S) -N- (3- {3-Fluoro-4- [4-methoxy-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 ] Oxazin-6-yloxy) -pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound is [5-bromo-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -yloxy) -pyrimidine-4. -Yl] -dimethyl-amine instead of 6- (5-bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine Prepared by following the same procedure as described for the preparation of Example 7 except that was used in ESI MS m / z 557.4 (M + H ^< + ^> ).
Example 17

  (S, S) -5- {4- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenyl} -2- (2-nitro-6,7- Dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -nicotinic acid methyl ester:

Step 1.5-Bromo-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -yloxy) -nicotinic acid methyl ester. The title compound was prepared by following the same procedure as described for the preparation of Example 7, except that 5-bromo-2-chloro-nicotinic acid methyl ester was used in place of 5-bromo-2-fluoro-pyridine. did. ESI MS m / z 399, 341 (bromine isotope, M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 8.55 (s, 1H), 8.28 (s, 1H), 8.01 (s , 1H), 5.77 (s, 1H), 4.66 (s, 2H), 4.42 (dd, J = 13.6, 4.0 Hz, 1H), 4.32 (d, J = 14 .0Hz, 1H), 3.60 (s, 3H).

Step 2. (S, S) -N- (3- {3-Fluoro-4- [4-methoxy-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 ] Oxazin-6-yloxy) -pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound is 5-bromo-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -yloxy) -nicotinic acid methyl ester Other than 6 (S)-(5-bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine Was prepared by following the same procedure as described for the preparation of Example 7. ESI MS m / z 571.5 (M + H ^< + ^> ).
Example 18

  (S, S) -5- {4- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenyl} -2- (2-nitro-6,7- Dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -nicotinic acid:

(S, S) -N- (3- {3-Fluoro-4- [4-methoxy-2- (2-nitro-6,7-dihydro-5H-imidazo [2,] in MeOH (5.0 ml). 1-b] [1,3] oxazin-6-yloxy) -pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide (20 mg, 0.035 mmol) and LiOH (50 mg, 2.0 mmol) as well as water (1.5 mL) was stirred at 40 ° C. for 2 h. The mixture was acidified with 1N HCl, extracted with EtOAc and concentrated in vacuo to give the title product as a yellow solid (15.0 mg, 77%). ESI MS m / z 563.3 (M + Li ⁺ ).
Example 19

  (S, S) -N- (3- {3-Fluoro-4- [4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxy) -pyrimidin-2-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1.6 (S)-(2-Chloro-pyrimidin-4-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine and 6 (S )-(4-Chloro-pyrimidin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. 2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -ol (452 mg, 2.44 mmol) and 2,4-dichloro- in DMF To a solution of pyrimidine (1.09 g, 7.32 mmol) was added NaH (200 mg, 5.0 mmol) at −60 ° C. under nitrogen. The mixture was slowly warmed to 0 ° C. and stirred at 0 ° C. for 3 hours. The reaction mixture was quenched with MeOH and EtOAc, washed with brine and concentrated in vacuo. The crude product was purified by flash chromatography eluting with hexane / EtOAc to give 6 (S)-(2-chloro-pyrimidin-4-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [ 2,1-b] [1,3] oxazine (367 mg) as a white solid, 6 (S)-(4-chloro-pyrimidin-2-yloxy) -2-nitro-6,7-dihydro-5H- Imidazo [2,1-b] [1,3] oxazine (120 mg) was obtained as a white solid. For both compounds, ESI MS m / z 297 (M + H ⁺ ) was obtained.

Step 2. (S, S) -N- (3- {3-Fluoro-4- [4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxy) -pyrimidin-2-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound is 6 (S)-(2-chloro-pyrimidin-4-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine 6 ( S)-(5-Bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Prepared by following the same procedure as described for the preparation of Example 7. ESI MS m / z 514 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 8.65 (d, J = 7.0 Hz, 1H), 8.23 to 8.18 (m, 2H), 8. 03 (s, 1H), 7.58 (dd, J = 14.4, 2.4 Hz, 1H), 7.44 (dd, J = 9.2, 2.4 Hz, 1H), 6.93 (d , J = 6.0 Hz, 1H), 5.89 (s, 1H), 4.78 to 4.70 (m, 3H), 4.49 to 4.44 (m, 2H), 4.17 (t , J = 9.0 Hz, 1H), 3.78 (dd, J = 8.8, 6.4 Hz, 1H), 3.41 (t, J = 5.4 Hz, 2H), 1.81 (s, 3H).
Example 20

  (S, S) -N- (3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxy) -pyrimidin-4-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

The title compound is 6 (S)-(4-chloro-pyrimidin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine 6 ( S)-(5-Bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Prepared by following the same procedure as described for the preparation of Example 7. ESI MS m / z 514 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 8.68 (d, J = 4.8 Hz, 1H), 8.22 to 8.15 (m, 2H), 8. 03 (s, 1H), 7.60 (dd, J = 14.4, 2.4 Hz, 1H), 7.56 (d, J = 4.4 Hz, 1H), 7.46 (dd, J = 8 .8, 1.6 Hz, 1H), 5.77 (s, 1H), 4.78 to 4.68 (m, 3H), 4.46 (s, 2H), 4.15 (t, J = 9) 0.0 Hz, 1H), 3.78 (dd, J = 8.8, 6.8 Hz, 1H), 3.40 (t, J = 5.6 Hz, 2H), 1.81 (s, 3H).
Example 21

  (S, S) -N- (3- {3-Fluoro-4- [5-methyl-6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 ] Oxazin-6-yloxy) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1.6 (S)-(5-Bromo-3-methyl-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine . The title compound was obtained by following the same procedure as described for the preparation of Example 7, except that 5-bromo-2-fluoro-3-methyl-pyridine was used instead of 5-bromo-2-fluoro-pyridine. Prepared. ESI MS m / z 355, 357 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 (s, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 5.68 (brs, 1H), 4.80 to 4.76 (m, 1H), 4.51 (d, J = 12.0 Hz, 1H), 4.39 to 4.36 (m, 2H), 2.09 (s, 3H).

Step 2. N- (3- {3-Fluoro-4- [4-methoxy-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 (S ) -Yloxy) -pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5 (S) -ylmethyl) -acetamide. The title compound is 6 (S)-(5-bromo-3-methyl-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazine was used in place of 6 (S)-(5-bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. Was prepared by following the same procedure as described for the preparation of Example 7. ESI MS m / z 527.3 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.56 (s, 1H), 7.49 (dd, J = 12 .8, 2.0 Hz, 1H), 7.38 (s, 1H), 7.32 (t, J = 8.4 Hz, 1H), 7.24 to 7.21 (m, 1H), 5.89 (T, J = 6.0 Hz, 1H), 5.73 (s, 1H), 4.78 to 4.75 (m, 2H), 4.48 (d, J = 12.8 Hz, 1H), 4 .36 (d, J = 2.4 Hz, 2H), 3.76 (dd, J = 9.2, 6.8 Hz, 1H), 3.66 to 3.59 (m, 2H), 2.10 ( s, 3H), 1.97 (s, 3H).
Example 22

  (S, S) -N- (3- {3-Fluoro-4- [2-methyl-6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 ] Oxazin-6-yloxy) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1.6 (S)-(5-Bromo-6-methyl-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine . The title compound was obtained by following the same procedure as described for the preparation of Example 7, except that 3-bromo-6-fluoro-2-methyl-pyridine was used instead of 5-bromo-2-fluoro-pyridine. Prepared. ESI MS m / z 355, 357 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 7.69 (d, J = 8.8 Hz, 1H), 7.42 (s, 1H), 6.50 ( d, J = 8.4 Hz, 1H), 5.72 (brs, 1H), 4.78 (dt, J = 12.4, 2.6 Hz, 1H), 4.50 (d, J = 12.4 Hz) , 1H), 4.36 (d, J = 3.2 Hz, 1H), 4.34 (t, J = 2.2 Hz, 1H), 2.54 (s, 3H).

Step 2. N- (3- {3-fluoro-4- [2-methyl-6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 (S ) -Yloxy) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5 (S) -ylmethyl) -acetamide. The title compound is 6- (5-bromo-6-methyl-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine 6 Example 7 except that-(5-bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine was used. Prepared by following the same procedure as described for the preparation of ESI MS m / z 527.3 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 8.23 (t, J = 5.6 Hz, 1H), 8.06 (s, 1H), 7.60- 7.55 (m, 2H), 7.40 to 7.35 (m, 2H), 6.77 (d, J = 8.8 Hz, 1H), 5.76 (brs, 1H), 4.74 to 4.67 (m, 3H), 4.47 (dd, J = 13.6, 2.8 Hz, 1H), 4.38 (d, J = 13.6 Hz, 1H), 4.15 (t, J = 9.2 Hz, 1H), 3.76 (dd, J = 8.8, 6.4 Hz, 1H), 3.41 (t, J = 6.2 Hz, 2H), 2.23 (s, 3H) 1.82 (s, 3H).
Example 23

  N- (3- {3-Fluoro-4- [5- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -pyridin-2-yl ] -Phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1.2- (6-Bromo-pyridin-3-yloxymethyl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole. The title compound was prepared by following the same procedure as described for the preparation of Example 10 except that 6-bromo-pyridin-3-ol was used in place of 5-bromo-pyridin-3-ol. ESI MS m / z 355, 357 (bromine isotope, M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (d, J = 3.6 Hz, 1H), 7.56 (s, 1H ), 7.39 (d, J = 8.8 Hz, 1H), 7.07 (dd, J = 8.4, 3.2 Hz, 1H), 4.48 (d, J = 10.4 Hz, 1H) 4.27 (d, J = 10.4 Hz, 1H), 4.14 (d, J = 10.4 Hz, 1H), 4.07 (d, J = 10.4 Hz, 1H), 1.79 ( s, 3H).

Step 2. N- (3- {3-Fluoro-4- [5- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -pyridin-2-yl ] -Phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound (mixture of two diastereomers) is 2- (6-bromo-pyridin-3-yloxymethyl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b ] Oxazole was used in place of 6 (S)-(5-Bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine Prepared by following the same procedure as described for the preparation of Example 7 except that ESI MS m / z 527.3 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 8.34 (d, J = 3.2 Hz, 1H), 8.23 (t, J = 5.8 Hz, 1H) ), 8.15 (s, 1H), 7.93 (t, J = 9.0 Hz, 1H), 7.71 (dd, J = 8.8, 1.2 Hz, 1H), 7.57 (dd , J = 14.4, 2.0 Hz, 1H), 7.47 (dd, J = 8.8, 2.8 Hz, 1H), 7.40 (dd, J = 8.8, 2.0 Hz, 1H). ) 4.76-4.71 (m, 1H), 4.43 (d, J = 2.4 Hz, 1H), 4.39 (d, J = 10.8 Hz, 1H), 4.19 (d , J = 10.4 Hz, 1H), 4.14 (t, J = 9.2 Hz, 1H), 3.76 (dd, J = 9.2, 6.8 Hz, 1H), 3.40 (t, J 5.4Hz, 2H), 1.81 (s, 3H), 1.69 (s, 3H).
Example 24

  (S, S) -N- (3- {3-Fluoro-4- [4- (4-methoxy-benzyloxy) -2- (2-nitro-6,7-dihydro-5H-imidazo [2,1 -B] [1,3] oxazin-6-yloxy) -pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1.5-Bromo-2-chloro-4- (4-methoxy-benzyloxy) -pyrimidine. To a solution of (4-methoxy-phenyl) -methanol (1.38 g, 10 mmol) and 5-bromo-2,4-dichloro-pyrimidine (4.6 g, 20 mmol) in THF at −15 ° C. under nitrogen. NaH (480 mg, 12 mmol) was added. The mixture was stirred at 15 ° C. for 2 hours. The reaction mixture was quenched with MeOH, diluted with EtOAc, washed with brine and concentrated in vacuo. The crude product was recrystallized from MeOH / H ₂ O to give the title compound as a yellow solid (1.0 g).

Step 2.6 (S)-[5-Bromo-4- (4-methoxy-benzyloxy) -pyrimidin-2-yloxy] -2-nitro-6,7-dihydro-5H-imidazo [2,1-b ] [1,3] Oxazine. The title compound was described for the preparation of Example 7 except that 5-bromo-2-chloro-4- (4-methoxy-benzyloxy) -pyrimidine was used in place of 5-bromo-2-fluoro-pyridine. Prepared by following the same procedure as ESI MS m / z 478, 480 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (s, 1H), 7.43 (s, 1H), 7.36 (d, J = 8 .4 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.56 (s, 1H), 5.39 (s, 2H), 4.82 (d, J = 12.0 Hz) , 1H), 4.51 (d, J = 12.8 Hz, 1H), 4.37 (s, 2H), 3.82 (s, 3H).

Step 3. (S, S) -N- (3- {3-Fluoro-4- [4- (4-methoxy-benzyloxy) -2- (2-nitro-6,7-dihydro-5H-imidazo [2,1 -B] [1,3] oxazin-6-yloxy) -pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound is 6 (S)-[5-bromo-4- (4-methoxy-benzyloxy) -pyrimidin-2-yloxy] -2-nitro-6,7-dihydro-5H-imidazo [2,1- b] [1,3] oxazine is converted to 6 (S)-(5-bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 Prepared by following the same procedure as described for the preparation of Example 7, except that it was used instead of oxazine. ESI MS m / z 650.8 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.20 (s, 1H), 7.54 (dd, J = 12.4, 2.0 Hz, 1H) 7.44 (s, 1H), 7.34 to 7.21 (m, 4H), 6.86 (d, J = 8.8 Hz, 1H), 6.00 (t, J = 6.4 Hz, 1H), 5.66 (brs, 1H), 5.35 (s, 2H), 4.85 (dd, J = 12.0, 2.8 Hz, 1H), 4.82 to 4.77 (m, 1H), 4.53 (d, J = 11.2 Hz, 2H), 4.06 (t, J = 9.0 Hz, 1H), 3.78 (s, 3H), 3.74 to 3.61 ( m, 3H), 2.02 (s, 3H).
Example 25

  (S, S) -N- (3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxy) -6-oxo-1,6-dihydro-pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

(S, S) -N- (3- {3-Fluoro-4- [4- (4-methoxy-benzyloxy) -2- (2-) in TFA / methylenene chloride (3.0 mL, 1/1). Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -A solution of acetamide (60 mg, 0.092 mmol) was stirred at room temperature for 1 hour. The solvent was evaporated and triturated with ether to give the title product as a pale yellow solid (43 mg, 88%). ESI MS m / z 530.4 (M + H ^< + ^> ).
Example 26

  (S, S) -N- (3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxy) -4-trifluoromethyl-pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1.6- (5-Bromo-4-trifluoromethyl-pyrimidin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. The title compound was 5-bromo-2-chloro-4-trifluoromethyl-pyrimidine (prepared as described by Ondi, 2004) except that 5-bromo-2-fluoro-pyridine was used instead. Prepared by following the same procedure as described for the preparation of Example 7. ESI MS m / z 410, 412 (bromine isotope, M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.87 (s, 1H), 7.46 (s, 1H), 5.66 ( s, 1H), 4.88 (d, J = 14.8 Hz, 1H), 4.57 (d, J = 12.8 Hz, 1H), 4.50 to 4.40 (m, 2H).

Step 2. (S, S) -N- (3- {3-Fluoro-4- [2-methyl-6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 ] Oxazin-6-yloxy) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound is 6 (S)-(5-bromo-4-trifluoromethyl-pyrimidin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1, 3] Oxazine instead of 6 (S)-(5-bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine Prepared by following the same procedure as described for the preparation of Example 7 except that it was used. ESI MS m / z 582.5 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.65 (s, 1H), 7.63 (d, J = 11.6 Hz, 1H), 7.48 (S, 1H), 7.32-7.25 (m, 2H), 6.02 (t, J = 6.2 Hz, 1H), 5.75 (s, 1H), 4.94 (d, J = 12.0 Hz, 1H), 4.83 to 4.82 (m, 1H), 4.60 (d, J = 12.4 Hz, 1H), 4.49 (brs, 2H), 4.10 (t , J = 9.8 Hz, 1H), 3.84 (t, J = 7.8 Hz, 1H), 3.72 to 3.62 (m, 2H), 2.04 (s, 3H).
Example 26

  (S, S) -N- {3- [2,6-difluoro-4 '-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxymethyl) -biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide:

Step 1.2-Nitro-6 (S)-[4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzyloxy] -6,7-dihydro -5H-imidazo [2,1-b] [1,3] oxazine. 2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-ol (420 mg, 2.28 mmol) and 2- (4) in DMF (10.0 mL). -Bromomethyl-phenyl) -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane (339 mg, 1.14 mmol) in a solution of NaH (137 mg, 3. 42 mmol, 60% dispersion in mineral oil). The mixture was slowly warmed to room temperature and stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with brine and concentrated in vacuo to give the title compound as a yellow solid (0.460 g, 89%). ESI MS m / z 402.4 (M + H ^< + ^> ).

Step 2. (S, S) -N- {3- [2,6-difluoro-4 '-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxymethyl) -biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide. 2-Nitro-6 (S)-[4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl in DMF / H2O (10 / 1.5.5 mL) ) -Benzyloxy] -6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine (160 mg, 0.40 mmol), N- [3- (3,5-difluoro-4- Iodo-phenyl) -2-oxo-oxazolidine-5 (S) -ylmethyl] -acetamide (158 mg, 0.40 mmol) (prepared as described by Das et al., WO 2006/038100 A1), Pd (Ph ₃ P ) ₄ (58 mg, 0.05 mmol) and a suspension of K ₂ CO ₃ (121 mg, 0.88 mmol) were degassed. The mixture was heated to 80 ° C. for 2.5 hours, diluted with EtOAc, washed with brine and concentrated in vacuo to give the crude product. The crude product was triturated with methylene chloride to give the title product (172 mg, 79%). ESI MS m / z 544.5 (M + H ^< + ^> ).
Example 27

  N- {3- [4- (6-Nitro-imidazo [2,1-b] -2 (3H) -8-aza-spiro [4.5] dec-8-yl) -3-fluorophenyl]- 2-Oxo-oxazolidine-5 (S) -ylmethyl} -acetamide:

Step 1. N- {3- [3-Fluoro-4- (1-oxa-6-aza-spiro [2.5] oct-6-yl) -phenyl] -2-oxo-oxazolidine-5 (S) -ylmethyl} -Acetamide. To a solution of trimethylsulfoxonium iodide (0.96 g, 4.35 mmol) in DMSO (10.0 mL) was added NaH (232 mg, 5.8 mmol, 60% dispersion in mineral oil) at room temperature. It was. The mixture is stirred at room temperature for 30 minutes, and N- {3- [3-fluoro-4- (4-oxo-piperidin-1-yl) -phenyl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide (WO2005). / Prepared as described by / 054234) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours, poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried and concentrated by vacuum to give the title product as a yellow solid (650 mg, 62%). ESI MS m / z 364 (M + H ^< + ^> ).

Step 2. N- (3- {4- [4- (2-Bromo-4-nitro-imidazol-1-ylmethyl) -4-hydroxy-piperidin-1-yl] -3-fluoro-phenyl} -2-oxo-oxazolidine -5 (S) -ylmethyl) -acetamide. N- {3- [3-Fluoro-4- (1-oxa-6-aza-spiro [2.5] oct-6-yl) -phenyl] -2-oxo-oxazolidine in acetonitrile (3.0 mL) A solution of −5 (S) -ylmethyl} -acetamide (100 mg, 0.275 mmol), 2-bromo-4-nitro-1H-imidazole (158 mg, 0.83 mmol), and triethylamine (0.40 mL) was added at 80 ° C. For 36 hours. The mixture was diluted with EtOAc and washed with brine to give the crude product, which was purified by flash chromatography to give the title product. This is used directly in the next step. ESI MS m / z 555, 557 (bromine isotope pattern, M + H ⁺ ).

Step 4. N- {3- [4- (6-Nitro-imidazo [2,1-b] -2 (3H) -8-aza-spiro [4.5] dec-8-yl) -3-fluorophenyl]- 2-Oxo-oxazolidine-5 (S) -ylmethyl} -acetamide. N- (3- {4- [4- (2-Bromo-4-nitro-imidazol-1-ylmethyl) -4-hydroxy-piperidin-1-yl] -3-fluoro- in DMF (3.0 mL) To a solution of phenyl} -2-oxo-oxazolidine-5 (S) -ylmethyl) -acetamide was added NaH (80 mg, 60% dispersion in mineral oil) at 0 ° C. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 1 hour. The reaction mixture was quenched by the addition of MeOH, diluted with EtOAc, washed with brine, dried and concentrated in vacuo to give the crude product. This was purified by flash chromatography to give the title product as a yellow oil (35 mg, 27% over two steps). ESI MS m / z 475 (M + H ^< + ^> ).
Example 28

  (S, R) -3- [2-Fluoro-4 ′-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl) -Biphenyl-4-yl] -5-hydroxymethyl-oxazolidine-2-one:

Step 1.5- (tert-Butyl-dimethyl-silanyloxymethyl) -3- [2-fluoro-4 ′-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [ 1,3] Oxazin-6-yloxymethyl) -biphenyl-4-yl] -oxazolidine-2-one. The title compound is 3- (4-bromo-3-fluoro-phenyl) -5 (S)-(tert-butyl-dimethyl-silanyloxymethyl) -oxazolidin-2-one as N- [3- (3 Prepared by following the same procedure as described for the preparation of Example 26 except that 5-difluoro-4-iodo-phenyl) -2-oxo-oxazolidine-5 (R) -ylmethyl] -acetamide was used. did. ESI MS m / z 599.6 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 8.00 (s, 1H), 7.56 (dd, J = 13.6, 2.4 Hz, 1H), 7.52 to 7.47 (m, 3H), 7.40 to 7.35 (m, 3H), 5.71 (s, 2H), 4.77 to 4.74 (m, 1H), 4. 67 to 4.62 (m, 3H), 4.43 (d, J = 11.6 Hz, 1H), 4.24 to 4.20 (m, 2H), 4.11 (t, J = 9.2 Hz) , 1H), 3.84 (dd, J = 11.6, 2.4 Hz, 1H), 3.79 (dd, J = 9.2, 5.2 Hz, 1H), 3.71 (dd, J = 11.6, 2.8 Hz, 1H), 0.74 (s, 9H), 0.002 (s, 3H), 0.000 (s, 3H).

Step 2. 3- [2-Fluoro-4 ′-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -yloxymethyl) -Biphenyl-4-yl] -5 (R) -hydroxymethyl-oxazolidine-2-one. 5 (R)-(tert-butyl-dimethyl-silanyloxymethyl) -3- [2-fluoro-4 ′-(2-nitro-6,7-dihydro-5H-imidazo) in THF (8.0 mL) To a solution of [2,1-b] [1,3] oxazin-6 (S) -yloxymethyl) -biphenyl-4-yl] -oxazolidin-2-one (70 mg, 0.117 mmol) was added TBAF (1 0.0 mL, 1.0 mmol, 1.0 M in THF) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with brine and purified by flash chromatography to give the title product as a yellow solid (36 mg, 64%). ESI MS m / z 485.3 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 8.03 (s, 1H), 7.60 (dd, J = 13.6, 2.4 Hz, 1H), 7.56-7.50 (m, 3H), 7.44-7.38 (m, 3H), 5.23 (t, J = 5.6 Hz, 1H), 4.74-4.66 (m , 4H), 4.46 (d, J = 12.0 Hz, 1H), 4.26 to 4.20 (m, 2H), 4.10 (t, J = 9.2 Hz, 1H), 3.85. (Dd, J = 8.8, 6.0 Hz, 1H), 3.68 to 3.64 (m, 1H), 3.58 to 3.52 (m, 1H).
Example 29

  (S, R) -3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -Pyrimidin-5-yl] -phenyl} -5-hydroxymethyl-oxazolidin-2-one:

Step 1.3- (4-Bromo-3-fluoro-phenyl) -5 (R) -hydroxymethyl-oxazolidine-2-one. Bromine (0.07 mL, 1.41 mmol) to 3- (3-fluoro-phenyl) -5 (R) -hydroxymethyl-oxazolidine-2-one (0.1 g, 0.47 mmol) in 2 mL of chloroform. The solution was added dropwise at room temperature. The reaction mixture was stirred for 3 hours at room temperature and the solvent was removed in vacuo. The residue was washed with saturated Na ₂ S ₂ O ₃ , brine and dried over Na ₂ SO ₄ . The solvent was removed and the residue was crystallized from ethyl acetate / hexane to give the title compound as a solid. ESI MS m / z 290 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43 (m, 2H), 7.01 (t, J = 21 Hz, 1H), 4.68 (m, 1H) ), 3.90 (m, 2H), 3.67 (m, 1H), 3.20 (bs, 1H).

Step 2. 3- (4-Bromo-3-fluoro-phenyl) -5 (R)-(tert-butyl-dimethyl-silanyloxymethyl) -oxazolidin-2-one. 3- (4-Bromo-3-fluoro-phenyl) -5 (R) -hydroxymethyl-oxazolidine-2-one (2.5 g, 8.6 mmol), TBSCl (1.7 g, 11.1 mmol) in THF And a solution of imidazole (0.76 g, 11.1 mmol) was stirred overnight. The reaction mixture was diluted with EtOAc, washed with brine and concentrated in vacuo to give the title compound as a white solid. ESI MS m / z 405 (M + H ^< + ^> ). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 (m, 2H), 7.10 (m, 1H), 4.61 (m, 1H), 3.93 (t, J = 23 Hz, 1H), 3.85 (m, 2H), 3.71 (dd, J = 7, 28 Hz, 1H), 0.76 (s, 9H), 0 (s, 6H).

Step 3.5 (R)-(tert-Butyl-dimethyl-silanyloxymethyl) -3- [3-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane -2-yl) -phenyl] -oxazolidine-2-one. 3- (4-Bromo-3-fluoro-phenyl) -5 (R)-(tert-butyl-dimethyl-silanyloxymethyl) -oxazolidine-2-one (4.45 g, 11.) in DMSO (100 mL). 0 mmol), PdCl ₂ dppf (1.346 g, 1.65 mmol), bis (pinacolato) diboron (3.92 g, 15.4 mmol) and potassium acetate (3.20 g) was degassed (3 ×), 80 Stir at 2.5 ° C. for 2.5 hours. The reaction mixture was diluted with EtOAc, washed with brine, dried and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography to give the title product as a white solid (5.73 g). ESI MS m / z 452.4 (M + H ^< + ^> ).

Step 4.5 (R)-(tert-butyl-dimethyl-silanyloxymethyl) -3- {3-fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2, 1-b] [1,3] Oxazin-6 (S) -yloxy) -pyrimidin-5-yl] -phenyl} -oxazolidine-2-one. The title compound is 5 (R)-(tert-butyl-dimethyl-silanyloxymethyl) -3- [3-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2]. Dioxaborolan-2-yl) -phenyl] -oxazolidine-2-one is converted to N- {3- [3-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane-2. Prepared by following the same procedure as described for the preparation of Example 8 except that it was used instead of -yl) -phenyl] -2-oxo-oxazolidine-5 (S) -ylmethyl} -acetamide. ESI MS m / z 587 (M + H ^< + ^> ).

Step 5. (S, R) -3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -Pyrimidin-5-yl] -phenyl} -5-hydroxymethyl-oxazolidin-2-one. The title compound is 5 (R)-(tert-butyl-dimethyl-silanyloxymethyl) -3- {3-fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2 , 1-b] [1,3] oxazin-6 (S) -yloxy) -pyrimidin-5-yl] -phenyl} -oxazolidine-2-one with 3- [2-fluoro-4 ′-(2-nitro -6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -yloxymethyl) -biphenyl-4-yl] -5 (R) -hydroxymethyl-oxazolidine Prepared by following the same procedure as described for the preparation of Example 28, but using instead of -2-one. ESI MS m / z 473 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 8.86 (s, 2H), 8.06 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.66 (t, J = 2.8 Hz, 1H), 7.47 (dd, J = 8.8, 2.4 Hz, 1H), 5.74 (s, 1H), 5.23 ( t, J = 5.6 Hz, 1H), 4.77 to 4.70 (m, 2H), 4.47 (s, 1H), 4.11 (t, J = 9.0 Hz, 1H); 86 (dd, J = 8.8, 6.0 Hz, 1H), 3.71 to 3.65 (m, 1H), 3.57 to 3.53 (m, 1H), 3.38 to 3.35 (M, 1H).
Example 30

  (S, R) -3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -Pyridin-3-yl] -phenyl} -5-hydroxymethyl-oxazolidin-2-one:

Step 1.5 (R)-(tert-butyl-dimethyl-silanyloxymethyl) -3- {3-fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2, 1-b] [1,3] Oxazin-6 (S) -yloxy) -pyridin-3-yl] -phenyl} -oxazolidine-2-one. The title compound is 6 (S)-(5-bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine 6 ( S)-(5-Bromo-pyrimidin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Except for use in place of oxazine Prepared by following the same procedure as described for the preparation of Example 29. ESI MS m / z 586.5 (M + H ^< + ^> ).

Step 2. (S, R) -3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -Pyridin-3-yl] -phenyl} -5-hydroxymethyl-oxazolidine-2-one. The title compound is 5 (R)-(tert-butyl-dimethyl-silanyloxymethyl) -3- {3-fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2 , 1-b] [1,3] oxazin-6 (S) -yloxy) -pyridin-3-yl] -phenyl} -oxazolidine-2-one described for the preparation of Example 28 Was prepared by following the same procedure. ESI MS m / z 472.3 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 8.06 (s, 1H), 7.94-7.91 (m, 1H), 7.63 (dt, J = 13.6, 2.4 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.46-7.43 (m, 1H), 6.97 (d, J = 9.2 Hz, 1H), 5.76 (s, 1H), 5.24 (t, J = 5.6 Hz, 1H), 4.74 to 4.67 (m, 2H) ), 4.48 to 4.38 (m, 2H), 4.13 to 4.09 (m, 1H), 3.86 (dd, J = 8.8, 6.0 Hz, 1H), 3.70 ˜3.64 (m, 1H), 3.56 to 3.52 (m, 1H), 3.14 (d, J = 5.2 Hz, 1H).
Example 31

  (S, S) -N- {3- [2-Fluoro-4 '-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yl Oxymethyl) -biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide:

Step 1.6 (S)-(4-Bromo-benzyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. 2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -ol (0.5 g, 2.7 mmol) and 4-bromobenzyl bromide ( A solution of 0.81 g, 3.24 mmol) was dissolved in DMF (50 ml) and treated with NaH (0.13 g, 3.24 mmol). The mixture was stirred for 4 hours at room temperature, diluted with water (100 ml) and extracted with EtOAc. The organic layer was separated, washed with water (2 ×), dried over Na ₂ SO ₄ and concentrated. The resulting gum was washed with hexane to remove unreacted benzyl bromide. The mixture was purified by preparative TLC. ESI MS m / z 356 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56-7.42 (m, 2H), 7.40 (s, 1H), 7.24-7.18 (M, 2H), 4.73 to 4.50 (m, 4H), 4.39 to 4.30 (m, 1H), 4.28 to 4.03 (m, 2H).

Step 2. (S, S) -N- {3- [2-Fluoro-4 '-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yl Oxymethyl) -biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide. 6 (S)-(4-Bromo-benzyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine (92 mg, 0.26 mmol), N- {3- [3-Fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -2-oxo-oxazolidine-5 (S)- ylmethyl} - acetamide (100 mg, 0.26 mmol) and _{K 2 CO 3 (72mg, 0.52mmol} ) and _{Pd (PPh} 3) combined 4 (45mg, 0.039mmol), DMF (5ml) and water (0.7 ml ). The mixture was heated to 75 ° C. for 4 hours and then poured into cold water (30 ml). The mixture was extracted with EtOAc, then dried over Na ₂ SO ₄ and concentrated. The oil was purified by preparative TLC to give 11 mg (1%) of product as a tan solid. ESI MS m / z 526 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28-8.22 (s, 1H), 7.61-7.25 (m, 7H), 4.80 To 4.62 (m, 4H), 4.50 to 4.40 (m, 1H), 4.30 to 4.08 (m, 1H), 4.31 to 4.08 (m, 2H), 3 .80 to 3.71 (m, 1H), 3.40 to 3.25 (m, 4H), 1.80 (s, 3H).
Example 32

  (S, S) -N- [3- (3-Fluoro-4- {4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxy) -acetyl] -piperazin-1-yl} -phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide:

Step 1. (2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -acetic acid tert-butyl ester. 2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -ol (0.5 g, 2.7 mmol) and bromo in DMF (10 ml) A solution of acetic acid tert-butyl ester (0.48 ml, 3.2 mmol) was treated with NaH (0.124 g, 3.2 mmol) and stirred at room temperature for 3 hours. The reaction was quenched by adding saturated ammonium chloride and the mixture was washed with EtOAc. The organic layer was washed with water, dried over Na ₂ SO ₄ and concentrated to give a white solid. The solid was filtered through silica gel to give the product as a white solid (1.86 g, 99%). ESI MS m / z 300 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 (s, 1H), 4.62 to 4.58 (m, 1H), 4.39 to 4.36 (M, 1H), 4.25 (s, 2H), 4.20 to 4.02 (m, 3H), 1.52 (s, 9H).

Step 2. (2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -yloxy) -acetic acid. ₂ -nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -yloxy) -acetic acid tert-butyl ester (5 ml) in CH ₂ Cl ₂ (5 ml) 1.2 g, 4.0 mmol) was treated with TFA (5 ml) and stirred for 1 hour at room temperature. The mixture was concentrated and a waxy solid (1.12 g) was used without further purification. ESI MS m / z 244 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 4.62 to 4.49 (m, 1H), 4.43 to 4.32. (M, 1H), 4.25 (s, 2H), 4.20 to 4.01 (m, 2H).

Step 3. N- [3- (3-Fluoro-4- {4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -Acetyl] -piperazin-1-yl} -phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide. (2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -acetic acid (53 mg, 0.22 mmol), N- [3- (3- Fluoro-4-piperazin-1-yl-phenyl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide (73 mg, 0.228 mmol) (prepared as described by Barbachyn et al., US Pat. No. 5,547,950) and TBTU (114 mg , 0.35 mmol) was dissolved in DMF (5 ml), treated with Et ₃ N (0.122 ml, 0.88 mmol) and stirred at room temperature for 12 hours. The mixture was diluted with EtOAc and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by preparative TLC to give 13 mg (10%) of the title product as a tan solid. ESI MS m / z 562 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50 (d, J = 11.6 Hz, 1H), 7.44 (s, 1H), 7.21-7 0.02 (m, 1H), 7.00 to 6.85 (m, 1H), 5.99 to 5.92 (m, 1H), 4.76 to 4.67 (m, 2H), 4.44 To 4.22 (m, 4H), 4.05 to 4.01 (m, 1H), 3.79 to 3.44 (m, 4H), 3.49 (s, 2H), 3.10 to 2 .62 (m, 4H), 2.02 (s, 3H), 1.24 (s, 3H).
Example 33

  N- (3- {3-Fluoro-4- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -piperazin-1-yl ] -Phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1. N- [3- (4- {4- [3- (2-Bromo-4-nitro-imidazol-1-yl) -2-hydroxy-2-methyl-propyl] -piperazin-1-yl} -3- Fluoro-phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide. N- [3- (3-Fluoro-4-piperazin-1-yl-phenyl) -2-oxo-oxazolidine-5 (S) -ylmethyl] -acetamide (335 mg, 0.99 mmol) (described by Barbachyn et al., US Pat. No. 5,547,950) A solution of 2-bromo-1- (2-methyl-oxiranylmethyl) -4-nitro-1H-imidazole (261 mg, 1 mmol) was heated to reflux in IPA for 4 hours. The mixture was concentrated to give N- [3- (4- {4- [3- (2-bromo-4-nitro-imidazol-1-yl) -2-hydroxy-2-methyl-propyl] -piperazine-1. -Yl} -3-fluoro-phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide and N- (3- {3-fluoro-4- [4- (2-methyl-6-nitro-2, A mixture of 3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -piperazin-1-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide was obtained (233 mg, 48%). The mixture was used in the next step without further purification. ESI MS m / z 518, 598 (M + H ^< + ^> ).

Step 2. N- (3- {3-Fluoro-4- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -piperazin-1-yl ] -Phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. N- [3- (4- {4- [3- (2-Bromo-4-nitro-imidazol-1-yl) -2-hydroxy-2-methyl-propyl] -piperazine-1 in DMF (10 ml) The above mixture containing -yl} -3-fluoro-phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide (233 mg, 0.39 mmol) was treated with NaH (39 mg, 0.97 mmol) at 60 ° C. Until 2 hours. The reaction mixture was cooled, diluted with saturated NH ₄ Cl (aq) and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by preparative TLC to give N- (3- {3-fluoro-4- [4- (2-methyl-6-nitro-2,3- Dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -piperazin-1-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide was obtained (48 mg, 24%). ESI MS m / z 518 (M + H ⁺ ); ¹ H NMR (400 MHz, CD ₃ OD) δ 7.82 (s, 1H), 7.4-7.25 (m, 1H), 7.0-6. 85 (m, 1H), 6.85 to 6.75 (m, 1H), 4.72 to 4.65 (m, 1H), 4.30 to 4.25 (m, 1H), 4.01 to 3.72 (m, 6H), 3.62 to 3.32 (m, 5H), 2.85 to 2.58 (m, 5H), 1.93 (s, 3H), 1.58 (s, 3H).
Example 34

  (S, R) -3- [2-Fluoro-4 ′-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl) -Biphen-4-yl] -5- [1,2,3] triazol-1-ylmethyl-oxazolidine-2-one:

  Step 1.5 (R) -Azidomethyl-3- (3-fluoro-4-iodo-phenyl) -oxazolidine-2-one. This title compound was prepared according to the procedure described in WO2006 / 022794.

Step 2. 3- (3-Fluoro-4-iodo-phenyl) -5 (R)-[1,2,3] triazol-1-ylmethyl-oxazolidine-2-one. To a solution of 5 (R) -azidomethyl-3- (3-fluoro-4-iodo-phenyl) -oxazolidin-2-one (770 mg, 2.138 mmol) in 1,4-dioxane (2 mL) was added bicyclo [2 2.1] hepta-2,5-diene (2.2 mL, 21.37 mmol) was added and the reaction mixture was heated in a sealed tube at 100 ° C. for 27 hours. The reaction mixture was cooled to room temperature, filtered, and the solid was washed with hexanes to give 610 mg (74%) of the title product as a light brown solid. LCMS (ESI) m / z 389 (M + H ^< + ^> ).

Step 3. (S, R) -3- [2-Fluoro-4 ′-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl) -Biphen-4-yl] -5- [1,2,3] triazol-1-ylmethyl-oxazolidine-2-one. 3- (3-Fluoro-4-iodo-phenyl) -5 (R)-[1,2,3] triazol-1-ylmethyl-oxazolidine-2-one (50 mg, 0.129 mmol), 2-nitro-6 (S)-[4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzyloxy] -6,7-dihydro-5H-imidazo [2,1 -B] [1,3] oxazine (62 mg, 0.155 mmol), K ₂ CO ₃ (136 mg, 0.258 mmol) and Pd (PPh ₃ ) ₄ (15 mg, 0.013 mmol) were combined and DMF (1 ml) and Suspended in water (0.1 ml). The mixture was heated to 60 ° C. for 5 hours and then quenched with saturated aqueous NH ₄ Cl (1 mL) at room temperature. The mixture was diluted with EtOAc (10 mL) and washed with water (5 mL × 5). The organic phase was dried (MgSO ₄ ) and concentrated. Column chromatography (2% MeOH / CH ₂ Cl ₂ ) gave 54 mg (78%) of the title product as a yellow solid. LCMS (ESI) m / z 536 (M + H ^< + ^> ).
Example 35

  (S, R) -3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy Methyl) -pyridin-3-yl] -phenyl} -5- [1,2,3] triazol-1-ylmethyl-oxazolidine-2-one:

3- (3-Fluoro-4-iodo-phenyl) -5 (R)-[1,2,3] triazol-1-ylmethyl-oxazolidine-2-one (90 mg, 0.232 mmol), 2-nitro-6 (S)-[5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyridin-2-ylmethoxy] -6,7-dihydro-5H-imidazo [ 2,1-b] [1,3] oxazine (108 mg, 0.278 mmol), K ₂ CO ₃ (244 mg, 0.464 mmol) and Pd (PPh ₃ ) ₄ (27 mg, 0.023 mmol) were combined and DMF ( 2 ml) and water (0.2 ml). The mixture was heated to 60 ° C. for 1 1/2 hours and then quenched with saturated aqueous NH ₄ Cl (2 mL) at room temperature. The mixture was diluted with EtOAc (10 mL) and washed with water (5 mL × 5). The organic phase was dried (MgSO ₄ ) and concentrated. Column chromatography (2% MeOH / CH ₂ Cl ₂ ) gave 60 mg (50%) of the title product as a yellow solid. LCMS (ESI) m / z 523 (M + H ^< + ^> ).
Example 36

  N- {3- [2-Fluoro-4 '-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -biphenyl-4-yl]- 2-Oxo-oxazolidine-5-ylmethyl} -acetamide:

In an oven-dried round bottom flask, N- {3- [3-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl]- 2-Oxo-oxazolidin-5-ylmethyl} -acetamide (78 mg, 0.2 mmol), 2- (4-Bromo-phenoxymethyl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1 -B] oxazole (prepared as described by Sasaki, H. et al .: Journal of Medicinal Chemistry (2006), 49 (26), 7854-7860; 71 mg, 0.2 mmol), Ph (PPh ₃ ) ₄ (23 mg, 0.02 mmol) and K ₂ CO ₃ (55 mg, 0.4 mmol) were added. The flask was flushed with nitrogen and 3 mL of degassed DMF / H ₂ O (10/1, v / v) was added. The resulting mixture was stirred at 80 ° C. for 3 h before being cooled and partitioned between 50 mL EtOAc / 50 mL water. The organic layer is washed with brine, dried over Na ₂ SO ₄ , concentrated, and purified by column chromatography (CH ₂ Cl ₂ / MeOH, v / v, 20: 1 to 10: 1) to give the title compound ( 70 mg) was obtained as an off-white solid. ESI MS m / z 526 (M + H). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.86 (s, 1H), 7.52 to 7.59 (m, 1H), 7.45 to 7.52 (m, 3H), 7.32 to 7.38 (m, 1H), 6.96 to 7.02 (m, 2H), 4.76 to 4.84 (m, 1H), 4.51 (d, J = 6.8 Hz, 1H), 4.38 (d, J = 6.8 Hz, 1H), 4.27 (d, J = 6.8 Hz, 1H), 4.18 (d, J = 6.8 Hz, 1H), 3.89 (s , 1H), 3.83 (dd, J = 6.8, 9.2 Hz, 1H), 3.55 to 3.59 (m, 2H), 1.96 (s, 3H), 1.77 (s) , 3H).
Example 37

  N- {3- [2-Fluoro-3 '-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -biphenyl-4-yl]- 2-Oxo-oxazolidine-5-ylmethyl} -acetamide:

The title compound is 2- (3-bromo-phenoxymethyl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole, 2- (4-bromo-phenoxymethyl)- Prepared by using the same procedure as described for Example 36 except that it was used instead of 2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole. The title compound was obtained as a pale solid (62 mg, about 60% yield). ESI MS m / z 526 (M + H); ¹ H NMR (400 MHz, acetone-d ₆ ) δ 7.84 (s, 1H), 7.63-7.70 (m, 1H), 7.56-7. 62 (m, 1H), 7.40 to 7.52 (m, 2H), 7.25 to 7.31 (m, 1H), 7.14 to 7.19 (m, 1H), 6.98 to 7.04 (m, 1H), 6.85 (b, 1H), 4.81 to 4.90 (m, 1H), 4.56 (d, J = 6.8 Hz, 1H), 4.45 ( d, J = 6.8 Hz, 1H), 4.35 (d, J = 6.8 Hz, 1H), 4.22 (d, J = 6.8 Hz, 1H), 4.20 (t, J = 9) .2 Hz, 1 H), 3.89 (dd, J = 6.8, 9.2 Hz, 1 H), 3.57 to 3.68 (m, 2 H), 1.99 (s, 3 H), 1.83 (S, 3H).
Example 38

  N- {3- [2′-chloro-2-fluoro-4 ′-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -biphenyl- 4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide:

The title compound is 2- (4-bromo-3-chloro-phenoxymethyl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole with 2- (4-bromo- Prepared by using the same procedure as described for Example 36 except that it was used instead of phenoxymethyl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole. did. The title compound was obtained as a pale solid (64 mg, about 57% yield). ESI MS m / z 560 (M + H).
Example 39

  N- {3- [3′-chloro-2-fluoro-4 ′-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -biphenyl- 4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide:

The title compound is 2- (4-bromo-2-chloro-phenoxymethyl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole, 2- (4-bromo- Prepared by using the same procedure as described for Example 36 except that it was used instead of phenoxymethyl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole. did. The title compound was obtained as a pale solid (64 mg, about 57% yield). ESI MS m / z 560 (M + H).
Example 40

  N- {3- [3′-cyano-2-fluoro-4 ′-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -biphenyl- 4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide:

The title compound is 5-bromo-2- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -benzonitrile as 2- (4-bromo- Prepared by using the same procedure as described for Example 36 except that it was used instead of phenoxymethyl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole. did. The title compound was obtained as a pale solid (35 mg, about 40% yield). ESI MS m / z 551 (M + H). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.64-7.70 (M, 1H), 7.56 (s, 1H), 7.23-7.32 (m, 2H), 6.96 ˜7.04 (m, 2H), 6.75 to 6.84 (m, 2H), 4.12 to 4.22 (m, 1H), 3.95 (q, J = 8.0 Hz, 2H) 3.87 (d, J = 11.2 Hz, 1H), 3.65 (d, J = 11.2 Hz, 1H), 3.57 (t, J = 8.0 Hz, 1H), 3.15 to 3.22 (m, 1H), 2.6-3.0 (m, 2H, overlapping with water peak), 1.25 (s, 3H), 1.14 (s, 3H).
Example 41

  N- (3- {2-fluoro-4 '-[(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -amino] -biphenyl-4 -Yl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1: (4-Iodo-phenyl)-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -amine. 2-Bromo-1- (2-methyl-oxiranylmethyl) -4-nitro-1H-imidazole (Goto, F. et al .: prepared as described by WO2004035547; 0.54 g, 2 mmol), 4- Iodoaniline (1.31 g, 6 mmol) and cobalt (II) chloride hexahydrate were suspended in 15 mL of acetonitrile and stirred at 60 ° C. for 3 hours. The resulting mixture was filtered through a celite pad and washed with EtOAc. After removing the solvent, a brown solid precipitated. The precipitate (about 200 mg) was dried and dissolved in 5 mL DMF. After the solution was cooled to −78 ° C., NaH (˜20 mg, 60% in mineral oil) was quickly added. The resulting mixture was allowed to warm to room temperature and stirred for 1 hour before being quenched with 1 mL water and partitioned between 50 mL EtOAc / 50 mL water. The organic layer was washed with brine and dried over Na ₂ SO ₄ . The concentrated residue was purified by aorum chromatography (EtOAc / hexane, v / v, 1/1 to 4/1) to give the title product (90 mg) as a yellow solid. ESI MS m / z 401 (M + H). ¹ H NMR (400 MHz, MeCN-d ₃ ) δ 7.66 (s, 1H), 7.39 (d, J = 5.2 Hz, 2H), 6.52 (d, J = 5.2 Hz, 2H) 4.75 to 4.91 (m, 1H), 4.20 (d, J = 10.4 Hz, 1H), 4.02 (d, J = 10.4 Hz, 1H), 3.37-3. 58 (m, 2H), 1.63 (s, 3H).

Step 2: N- (3- {2-Fluoro-4 '-[(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -amino]- Biphenyl-4-yl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound is (4-iodo-phenyl)-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -amine with 2- (4-bromo Example 36 except that -phenoxymethyl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole was used and the reaction was carried out at 50 ° C. for 1 hour. Prepared by using the same procedure as described. The title compound was obtained as a pale solid (60 mg, about 80% yield). ESI MS m / z 525 (M + H).
Example 42

  (S, S) -N- (3- {3-Fluoro-4- [3- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxy) -propenyl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide.

Step 1: (Z) -6 (S)-(3-Bromo-allyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine and (E) -6 (S)-(3-Bromo-allyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. 2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -ol (380 mg, 2 mmol) and 1,3-dibromopropene in 5 mL DMF After cooling a solution of (trans-cis mixture, 0.3 mL, 3 mL) to −78 ° C., NaH (˜120 mg, 60% in mineral oil) was quickly added. The resulting mixture was allowed to warm to room temperature and stirred for 3 h before being quenched with 1 mL water and partitioned between 50 mL EtOAc / 50 mL water. The organic layer was washed with brine and dried over Na ₂ SO ₄ . Column chromatography (dichloromethane / methanol, v / v, 20/11) gave the title product (E isomer, 125 mg) as a yellow solid. ESI MS m / z 306 (M + H). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.31 (s, 1H), 6.33 (d, J = 7.6 Hz, 1H), 6.19 (q, J = 7.6 Hz, 1H), 4 .49-4.56 (m, 1H), 3.96-4.32 (m, 6H). A mixture (260 mg) of the E / Z isomer of the title compound was also obtained. The Z isomer of the title compound is obtained after preparative TLC separation.

Step 2: (Z) -N- (3- {3-Fluoro-4- [3- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine- 6-yloxy) -propenyl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound is 6 (S)-(3-bromo-allyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine with 2- (4-bromo By using the same procedure as described for Example 36 except that -phenoxymethyl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole was used. Prepared. The title compound was obtained as an off-white solid (55 mg, 62% yield). ESI MS m / z 476 (M + H). ). ¹ H NMR (400 MHz, DMF-d ₄ ) 8.29 (t, J = 5.6 Hz, 1H), 8.07 (s, 1H), 7.68 (t, J = 8.8 Hz, 1H), 7.58 (dd, J = 2.0, 13.6 Hz, 1H), 7.35 (dd, J = 2.0, 8.8 Hz, 1H), 6.75 (d, J = 16.4 Hz, 1H), 6.47 (dt, J = 16.4, 6.0 Hz, 1H), 4.86 (b, 1H), 4.77 (d, J = 11.6 Hz, 1H), 4.63 ( d, J = 12.4 Hz, 1H), 4.36 to 4.50 (m, 5H), 4.25 (t, J = 8.8 Hz, 1H), 3.90 (dd, J = 6.4). , 9.2 Hz, 1H), 3.56 to 3.64 (m, 2H), 1.92 (s, 3H).
Example 43

  (E) -N- (3- {3-Fluoro-4- [3- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 (S ) -Yloxy) -propenyl] -phenyl} -2-oxo-oxazolidine-5 (S) -ylmethyl) -acetamide:

The title compound is (E) -6- (3-bromo-allyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine 2- (4- Bromo-phenoxymethyl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] Use the same procedure as described for Example 36, except that it was used instead of oxazole. It was prepared by. The title compound was obtained as an off-white solid (80 mg, 88% yield). ESI MS m / z 476 (M + H); ¹ H NMR (400 MHz, MeCN-d ₃ ) 7.71 (s, 1H), 7.59 (d, J = 12.8 Hz, 1H), 7.32-7 .42 (m, 2H), 6.87 (b, 1H), 6.72 (d, J = 11.6 Hz, 1H), 6.01 (dt, J = 11.6, 4.8 Hz, 1H) 4.86 (b, 1H), 4.63 to 4.69 (m, 1H), 4.39 to 4.48 (m, 2H), 4.46 (d, J = 12.0 Hz, 1H) 4.20 to 4.28 (m, 3H), 4.18 (t, J = 8.8 Hz, 1H), 3.87 (dd, J = 9.2, 6.4 Hz, 1H), 3. 64 (t, J = 5.6 Hz, 1H), 2.00 (s, 3H).
Example 44

  N- (3- {3-Fluoro-4- [1- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -yloxy Methyl) -vinyl] -phenyl} -2-oxo-oxazolidine-5 (S) -ylmethyl) -acetamide:

Step 1: 6 (S)-(2-Bromo-allyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. The title compound was prepared by using the same procedure as described for Example 42, Step 1, except that 2,3-dibromopropene was used instead. The title compound was obtained as a yellow solid (220 mg, 45% yield). ESI MS m / z 306 (M + H). ¹ H NMR (400 MHz, acetone-d ₆ ) δ 7.78 (s, 1 H), 6.03 (s, 1 H), 5.65 (s, 1 H), 4.69 (d, J = 12.0 Hz) , 1H), 4.58 (d, J = 12.0 Hz, 1H), 4.34 to 4.46 (m, 5H).

Step 2: N- (3- {3-Fluoro-4- [1- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy Methyl) -vinyl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. The title compound is 6- (2-bromo-allyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine and 2- (4-bromo-phenoxymethyl). ) Prepared by using the same procedure as described for Example 36 except that it was used instead of 2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole. The title compound was obtained as a brown solid (252 mg, 74% yield). ESI MS m / z 476 (M + H). ). ¹ H NMR (400 MHz, MeCN-d ₃ ) 7.64 (s, 1H), 7.56 (dd, J = 13.6, 2.0 Hz, 1H), 7.46 (t, J = 8.8 Hz) , 1H), 7.2 (dd, J = 8.8, 2.4 Hz, 1H), 6.86 (b, 1H), 5.60 (s, 1H), 5.55 (s, 1H), 4.80 to 4.88 (m, 1H), 4.54 to 4.63 (m, 3H), 4.45 (d, J = 11.2 Hz, 1H), 4.16 to 4.27 (m 3H), 4.15 (t, J = 9.2 Hz, 1H), 3.84 (dd, J = 6.4, 9.2 Hz, 1H), 3.56 to 3.66 (m, 2H) 3.39 (d, J = 5.6 Hz, 1H), 1.99 (s, 3H).
Example 45

  N- (3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -acetyl] -Phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

N- (3- {3-Fluoro-4- [1- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl)- Vinyl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide (48 mg) was dissolved in 1.5 mL of methanol followed by NaIO ₄ (54 mg) and OsO ₄ (0.02 mL, 2. 5%) was added. The solution was stirred at room temperature for 4 hours, after which celite (about 500 mg) was added. The resulting mixture was stirred for 30 minutes before being filtered and washed with EtOAc. The organic layer was dried over Na ₂ SO ₄ and purified by preparative TLC (CH ₂ Cl ₂ / MeOH, v / v, 10/1). The title compound was obtained as a yellow solid (8 mg). ESI MS m / z 478 (M + H). ¹ H NMR (400 MHz, MeCN-d ₃ ) 8.06 (t, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.69 (dd, J = 14.0, 2.0 Hz) , 1H), 7.52 (dd, J = 8.8, 2.4 Hz, 1H), 6.84 (b, 1H), 4.95 to 5.00 (m, 2H), 4.83 to 4 .92 (m, 1H), 4.78 (dt, J = 12.0, 2.8 Hz, 1H), 4.53 (d, J = 12.8 Hz, 1H), 4.41 (dt, J = 12.8, 2.0 Hz, 1H), 4.30 to 4.35 (m, 1H), 4.29 (dd, J = 12.8, 3.2 Hz, 1H), 4.21 (t, J = 9.2 Hz, 1H), 3.89 (dd, J = 9.2, 6.4 Hz, 1H), 3.58 to 3.68 (m, 2H), 3.39 (d, J = 5. 2Hz, 1H), 1.98 (s, 3H).
Example 46

  N- (3- {3-Fluoro-4- [1-hydroxy-1-hydroxymethyl-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazine-6-yloxy) -ethyl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

The title compound is N- (3- {3-fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 ] Oxazin-6-yloxy) -acetyl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide. A disterosteric mixture of the title compound was obtained as a white solid (16 mg). ESI MS m / z 510 (M + H).
Example 47

  (S, S) -N- (3- {3-Fluoro-4- [3- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxy) -prop-1-ynyl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1: 2-Nitro-6 (S) -prop-2-ynyloxy-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. The title compound was prepared by using the same procedure as described for Example 42, Step 1, except that 3- (trimethylsilyl) propargyl bromide was used instead. The title compound was obtained as an orange solid (155 mg, 34% yield). ESI MS m / z 224 (M + H). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 (s, 1H), 4.62 (dq, J = 12.8, 2.0 Hz, 1H), 4.30 to 4.42 (m, 2H) 4.33 (t, J = 2.4 Hz, 2H), 4.23 (d, J = 4.0 Hz, 1H), 4.22 (t, J = 2.4 Hz, 1H), 2.55 ( t, J = 2.4 Hz, 1H).

Step 2: (S, S) -N- (3- {3-Fluoro-4- [3- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazine-6-yloxy) -prop-1-ynyl] -phenyl} -2-oxo-oxazolidin-5-ylmethyl) -acetamide. An oven-dried round bottom flask was charged with 2-nitro-6 (S) -prop-2-ynyloxy-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine (75 mg, 0 .34 mmol), N- [3- (3-Fluoro-4-iodo-phenyl) -2-oxo-oxazolidine-5 (S) -ylmethyl] -acetamide (127 mg, 0.34 mmol), PhCl ₂ (PPh ₃ ) ₂ (23 mg, 0.02 mmol) and CuI (3.2 mg, 0.017 mmol) were added. After the flask was flushed with nitrogen, degassed DMF (4 mL) and Et ₃ N (0.15 mL, 1.05 mmol) were added. The resulting mixture was stirred at 80 ° C. for 1 h, then cooled and partitioned between 50 mL EtOAc / 50 mL water. The organic layer was washed with brine and dried over Na ₂ SO ₄ . Column chromatography of the concentrated residue (CH ₂ Cl ₂ / MeOH, v / v, 20: 1 to 10: 1) gave the title compound (60 mg) as a yellow solid. ESI MS m / z 474 (M + H). ¹ H NMR (400 MHz, MeCN-d ₃ ) 7.73 (s, 1H), 7.65 (dd, J = 12.4, 2.4 Hz, 1H), 7.59 (t, J = 8.4 Hz) , 1H), 7.39 (dd, J = 8.8, 2.4 Hz, 1H), 6.84 (b, 1H), 4.20 to 4.99 (m, 1H), 4.76 (dt) , J = 12.4, 2.8 Hz, 1H), 4.67 (s, 2H), 4.53 (d, J = 12.8 Hz, 1H), 4.45 to 4.51 (m, 1H) 4.26 to 4.42 (m, 2H), 4.17 (t, J = 9.2 Hz, 1H), 3.85 (dd, J = 9.6, 5.2 Hz, 1H), 3. 56-3.68 (m, 2H), 1.98 (s, 3H).
Example 48

  (S, S) -N- {3- [2,2′-difluoro-5 ′-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine- 6-yloxymethyl) -biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide:

Step 1.6 (S)-(3-Bromo-4-fluoro-benzyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. The title compound was prepared by following the same procedure as described for the preparation of Example 2, Step 1. ESI MS m / z 374 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.39 (d, J = 15 Hz, 1H), 7.18 (m, 1H) ), 7.06 (m, 1H), 4.57 (m, 3H), 4.34 (m, 1H), 4.15 (m, 3H).

Step 2. (S, S) -N- {3- [2,2′-difluoro-5 ′-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine- 6-yloxymethyl) -biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide. The title compound was 6 (S)-(3-bromo-4-fluoro-benzyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine 6 (S)-(5-Bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazine was used instead of Prepared by following the same procedure as described for the preparation of Example 7, Step 2. ESI MS m / z 544 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.19 (m, 7H), 4.55 (m, 3H), 4.07 (m, 4H), 4. 50 (m, 4H), 2.88 (m, 2H), 1.90 (m, 3H).
Example 49

  (S, S) -N- {3- [2-Fluoro-3 '-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-loxymethyl ) -Biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide.

The title compound is 6 (S)-(3-bromo-benzyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine 6 (S)- Example 7, except that it was used instead of (5-bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. Prepared by following the same procedure as described for the preparation of Step 2. ESI MS m / z 526 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33 (m, 8H), 4.60 (m, 3H), 4.28 (m, 1H), 4. 04 (m, 4H), 3.73 (m, 1H), 3.56 (s, 2H), 2.51 (bs, 2H), 1.94 (d, J = 15 Hz, 3H).
Example 50

  N- {3- [3-Fluoro-4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -phenyl] -2-oxo-oxazolidine -5-ylmethyl} -acetamide.

The title compound was prepared except that N- [3- (3-fluoro-4-hydroxy-phenyl) -2-oxo-oxazolidine-5 (S) -ylmethyl] -acetamide was used in place of 4-bromophenol. Example 36, 2- (4-Bromo-phenoxymethyl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole (Sasaki, H. et al .: Journal of Medicinal Chemistry (2006) ), 49 (26), prepared as described by 7854-7860) by following the same procedure as described for the preparation. Product isolated as a solid. ESI MS m / z 450 (M + H ^< + ^> ).
Example 51

  N-(((5S) -3- (3-Fluoro-4- (2-((2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) methoxy ) Pyrimidin-5-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide:

Step 1: 2-((5-Bromopyrimidin-2-yloxy) methyl) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole. (2-Methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazol-2-yl) -methanol (0.10 g, 0.50 mmol), 5-bromo-2-chloropyrimidine (0 .16 g, 0.82 mmol) and NaH (about 30 mg, 60% in mineral oil) were suspended in 2 mL DMF and stirred at room temperature for 2 hours. The resulting mixture was diluted with 150 mL EtOAc and washed with 100 mL NaHCO ₃ and 100 mL water. The aqueous layer was extracted again with 100 mL EtOAc. The organic layer was washed with brine and dried over Na ₂ SO ₄ . The concentrated residue was purified by column chromatography (DCM / MeOH, 0-3%) to give the title compound (152 mg, 83%) as a white solid. APCI MS m / z 356.6, 358.6 (M + H). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.77 (s, 2H), 8.14 (s, 1H), 4.61 (s, 2H), 4.41 (d, J = 11 .1 Hz, 1 H), 4.20 (d, J = 11.1 Hz, 1 H), 1.70 (s, 3 H).

Step 2: N-(((5S) -3- (3-Fluoro-4- (2-((2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole-2- Yl) methoxy) pyrimidin-5-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) -acetamide. (S) -N-((3- (3-fluoro-4-) in toluene (2.5 mL), EtOH (1.5 mL), DMF (4 mL) and K ₂ CO ₃ (2M, 1 mL, 2 mmol). (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (0.14 g, 0.37 mmol) and 2 To a mixture of-((5-bromopyrimidin-2-yloxy) methyl) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole (0.105 g, 0.29 mmol), Nitrogen was purged. PdCl ₂ (dppf) (12 mg, 0.015 mmol) was added and the mixture was refluxed under nitrogen for 1 h (100 ° C.) and then partitioned between EtOAc (150 mL) and water (100 mL). The aqueous layer was extracted again with 100 mL EtOAc. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), evaporated and column chromatography (DCM / MeOH, 0-5%) using gradient elution gave the title compound as a brown solid. (60 mg, 39%). APCI MS m / z 528.3 (M + H). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.81 (d, J = 1.3 Hz, 2H), 8.22 (t, J = 5.8 Hz, 1H), 8.16 (s, 1H), 7.68 (t, J = 8.8 Hz, 1H), 7.65 (dd, J = 13.4, 2.2 Hz, 1H), 7.45 (dd, J = 8.6, 2 .2 Hz, 1 H), 4.81 to 4.73 (m, 1 H), 4.71 (d, J = 11.9 Hz, 1 H), 4.67 (d, J = 11.9 Hz, 1 H), 4 .45 (d, J = 11.0 Hz, 1H), 4.23 (d, J = 11.0 Hz, 1H), 4.18 (t, J = 9.1 Hz, 1H), 3.79 (dd, J = 9.2, 6.4 Hz, 1H), 3.44 (t, J = 5.5 Hz, 2H), 1.84 (s, 3H), 1.73 (s, 3H).
Example 52

  N-(((S) -3- (3-Fluoro-4- (5-(((S) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 ] -Oxazin-6-yloxy) methyl) pyridin-3-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide:

Step 1: (6S) -6-[(5-Bromopyridin-3-yl) methoxy] -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. (S) -2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-ol (3.63 g, 19.) in dry DMF (80 mL). 6 mmol) and 3-bromo-5- (chloromethyl) pyridine hydrochloride (4.78 g, 19.6 mmol, 1 eq) was added 60% NaH (1.88 g, 47 mmol, 2.4 eq) in mineral oil. ) And then stirred at room temperature overnight (16 hours), quenched with water (150 mL) and extracted with EtOAc. Chromatography of the crude product on silica gel, eluting with MeOH / CH ₂ Cl ₂ (1:19), gave the title product (2.10 g, 30%) as a white solid. APCI MS m / z 355.7, 357.7 (M + H). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.64 (d, J = 2.3 Hz, 1H), 8.52 (d, J = 1.7 Hz, 1H), 8.03 (s, 1H), 7.97 (br t, J = 2.1 Hz, 1H), 4.73 (d, J = 12.6 Hz, 1H), 4.70 to 4.65 (m, 2H), 4.48 (D, J = 12 Hz, 1H), 4.31 to 4.20 (m, 3H).

Step 2: N-(((S) -3- (3-Fluoro-4- (5-(((S) -2-nitro-6,7-dihydro-5H-imidazo- [2,1-b] [1,3] Oxazin-6-yloxy) methyl) pyridin-3-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide. The title compound is (6S) -6-[(5-bromopyridin-3-yl) methoxy] -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine Was used in place of 2-((5-bromopyrimidin-2-yloxy) methyl) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole. Prepared by following the same procedure as described for the preparation of Step 2. APCI MS m / z 527.4 (M + H). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.69 (t, J = 1.8 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.22 (t, J = 5.8 Hz, 1H), 8.01 (s, 1H), 7.88 (d, J = 1.4 Hz, 1H), 7.66-7.59 (m, 2H), 7.45 ( dd, J = 8.6, 2.2 Hz, 1H), 4.82 to 4.73 (m, 3H), 4.69 (dt, J = 12.0, 2.5 Hz, 1H), 4.49. (D, J = 11.6 Hz, 1H), 4.34 to 4.28 (m, 2H), 4.25 (dd, J = 13.6, 3.4 Hz, 1H), 4.18 (t, J = 9.0 Hz, 1H), 3.80 (dd, J = 9.2, 6.4 Hz, 1H), 3.44 (t, J = 5.5 Hz, 2H), 1.84 (s, 3H) ).
Example 53

  N-(((S) -3- (3-Fluoro-4- (2-(((S) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 ] -Oxazin-6-yloxy) methyl) pyridin-4-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide:

Step 1: 4-Bromo-2- (chloromethyl) pyridine. CH ₂ Cl ₂ (210mL) solution of 4-bromo-2-pyridylmethanol (3.38 g, 0.016 mol) in a solution _of, SOCl 2 and (21 mL) was added slowly at 0 ° C.. The mixture was warmed to room temperature and stirred for 20 hours, after which saturated NaHCO ₃ was added. The organic layer was washed with brine, dried (MgSO ₄ ) and concentrated to give crude 4-bromo-2- (chloromethyl) pyridine (2.93 g, 79%) as a yellow oil. APCI MS m / z 205.7, 207.7 (M + H). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.47 (d, J = 5.3 Hz, 1H), 7.68 (d, J = 1.7 Hz, 1H), 7.42 (dd, J = 5.3, 1.75 Hz, 1H), 4.64 (s, 2H).

Step 2: (6S) -6-[(4-Bromopyridin-2-yl) methoxy] -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. (S) -2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-ol (2.87 g, 15.) in dry DMF (60 mL). 5 mmol) and 4-bromo-2- (chloromethyl) pyridine (2.91 g, 14 mmol) were diluted with NaH (0.68 g of a 60% dispersion in mineral oil, 16.9 mmol,) to 0. Treated at ˜5 ° C. and the mixture was stirred at room temperature for 3 h before being quenched with water (150 mL) and extracted with EtOAc (6 × 150 mL). The organic layer was dried (MgSO ₄ ), evaporated and chromatographed on silica gel eluting with MeOH / EtOAc (1:19) to give the title compound (2.701 g, 54%) as a pale yellow solid. Obtained. APCI MS m / z 355.7, 357.7 (M + H). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.41 (d, J = 5.3 Hz, 1H), 8.01 (s, 1H), 7.59 (dd, J = 5.3) 1.9 Hz, 1H), 7.55 (d, J = 1.5 Hz, 1H), 4.78 to 4.68 (m, 3H), 4.50 (d, J = 12.0 Hz, 1H), 4.35 to 4.22 (m, 3H).

Step 3: N-(((S) -3- (3-Fluoro-4- (2-(((S) -2-nitro-6,7-dihydro-5H-imidazo- [2,1-b] [1,3] -Oxazin-6-yloxy) methyl) pyridin-4-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide. The title compound is (6S) -6-[(4-bromopyridin-2-yl) methoxy] -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine Was used in place of 2-((5-bromopyrimidin-2-yloxy) methyl) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole. Prepared by following the same procedure as described for the preparation of Step 2. APCI MS m / z 527.4 (M + H). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.60 (br d, J = 5.9 Hz, 1H), 8.27 (t, J = 5.8 Hz, 1H), 8.03 (s , 1H), 7.65 (t, J = 8.8 Hz, 1H), 7.63 (dd, J = 13.8, 2.2 Hz, 1H), 7.53 to 7.49 (m, 2H) 7.45 (dd, J = 8.6, 2.2 Hz, 1H), 4.82 (d, J = 13.4 Hz, 1H), 4.78 (d, J = 13.4 Hz, 1H), 4.80 to 4.74 (m, 1H), 4.71 (dt, J = 12.0, 2.5 Hz, 1H), 4.50 (d, J = 11.8 Hz, 1H), 4.39 ˜4.30 (m, 2H), 4.24 (dd, J = 13.4, 3.1 Hz, 1H), 4.17 (t, J = 9.1 Hz, 1H), 3.79 (dd, J = 9. 2, 6.5 Hz, 1H), 3.44 (t, J = 5.5 Hz, 2H), 1.84 (s, 3H).
Example 54

  N-(((S) -3- (3-Fluoro-4- (4-(((S) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 ] -Oxazin-6-yloxy) methyl) pyridin-2-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide:

Step 1: 2-Bromo-4- (bromomethyl) pyridine hydrobromide. (2-Bromo-4-pyridyl) methanol (2.00 g, 10.6 mmol) was dissolved in dry CH ₂ Cl ₂ (10 mL) and then SOBr ₂ (0.90 mL, 11.7 mmol) was added at 0 ° C. . The reaction mixture was stirred overnight, after which the solvent was evaporated and the residue was crystallized from MeOH-Et ₂ O to give the title compound (2.81 g, 79%) as a white solid. APCI MS m / z 252.2 (M + H). ¹ H-NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.39 (d, J = 5.0 Hz, 1H), 7.74 (d, J = 0.9 Hz, 1H), 7.51 (dd , J = 5.0, 1.4 Hz, 1H), 4.66 (s, 2H).

Step 2: (S) -6-((2-Bromopyridin-4-yl) methoxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. The title compound was described for the preparation of Example 53, Step 2, except that 2-bromo-4- (bromomethyl) pyridine hydrobromide was used in place of 4-bromo-2- (chloromethyl) pyridine. Prepared by following the same procedure as APCI MS m / z 355.7, 357.7 (M + H). ¹ H-NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.34 (dd, J = 4.8, 0.4 Hz, 1H), 8.02 (s, 1H), 7.51 (d, J = 0.4 Hz, 1H), 7.35 (dt, J = 5.1, 0.6 Hz, 1H), 4.75 (d, J = 14.1 Hz, 1H), 4.72 to 4.65 ( m, 2H), 4.49 (d, J = 12.0 Hz, 1H), 4.31-4.21 (m, 3H).

Step 3: N-(((S) -3- (3-Fluoro-4- (4-(((S) -2-nitro-6,7-dihydro-5H-imidazo- [2,1-b] [1,3] -Oxazin-6-yloxy) methyl) pyridin-2-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide. The title compound is (S) -6-((2-bromopyridin-4-yl) methoxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine Was used in place of 2-((5-bromopyrimidin-2-yloxy) methyl) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole. Prepared by following the same procedure as described for the preparation of Step 2. APCI MS m / z 527.4 (M + H). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.65 (dd, J = 5.0, 0.5 Hz, 1H), 8.27 (t, J = 5.8 Hz, 1H), 8. 04 (s, 1H), 8.00 (t, J = 8.9 Hz, 1H), 7.67 (br s, 1H), 7.60 (dd, J = 14.2, 2.2 Hz, 1H) 7.45 (dd, J = 8.7, 2.2 Hz, 1H), 7.29 (dd, J = 5.0, 1.3 Hz, 1H), 4.81 (d, J = 13.9 Hz) , 1H), 4.77 (d, J = 13.9 Hz, 1H), 4.79 to 4.72 (m, 1H), 4.70 (dt, J = 12.0, 2.5 Hz, 1H) 4.50 (d, J = 11.9 Hz, 1H), 4.35 to 4.21 (m, 3H), 4.18 (t, J = 9.0 Hz, 1H), 3.80 (dd, J = 9.2 , 6.5 Hz, 1H), 3.44 (t, J = 5.5 Hz, 2H), 1.84 (s, 3H).
Example 55

  N-(((S) -3- (3-Fluoro-4- (6-(((S) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 ] -Oxazin-6-yloxy) methyl) pyridin-2-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide:

Step 1: 6-Bromo-2- (chloromethyl) pyridine. N-butyllithium (10 mL, 25.32 mmol, 2.5 M solution in hexane) was added over 20 minutes at −78 ° C. with 2,5-dibromopyridine (5.0 g, 21 in toluene (250 mL). .1 mmol) was added dropwise to the degassed solution, and then the solution was stirred for 2 hours at -78 ° C. Then, DMF (2.1 mL, 27.43 mmol) was added dropwise, and the reaction was allowed to stand at −78 ° C. for 1 hour. MeOH (20 mL) and NaBH ₄ (1.60 g, 42.2 mmol) were then added at −78 ° C., the reaction mixture was allowed to slowly reach room temperature and stirring was continued for 16 h. Saturated aqueous NH ₄ Cl (100 mL) was added at −10 ° C. and stirring was continued for 30 minutes. The two layers were separated. The toluene layer was concentrated and dried under vacuum to give 6-bromo-2-pyridinyl) methanol (3.74 g, 94%) as a pale yellow oil. A solution of this oil (3.74 g, 19.8 mmol) in CHCl ₃ (250 mL) was treated with SOCl ₂ (25 mL) at 0 ° C., after which the reaction mixture was refluxed for 1 h and poured into ice water. ^and extracted with i Pr ₂ O. The combined organic layers were washed with brine, dried (MgSO ₄ ) and concentrated to dryness to give the title compound as a yellow oil (3.42 g, 83%). APCI MS m / z 205.9, 207.9 (M + H). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (t, J = 7.7 Hz, 1H), 7.47 (d, J = 7.4 Hz, 1H), 7.44 (d, J = 7. 9 Hz, 1H), 4.63 (s, 2H).

Step 2: (6S) -6-[(6-Bromopyridin-2-yl) methoxy] -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. The title compound is the same procedure as described for the preparation of Example 53, Step 2, except that 6-bromo-2- (chloromethyl) pyridine was used in place of 4-bromo-2- (chloromethyl) pyridine. Prepared by following APCI MS m / z 355.7, 357.7 (M + H). ¹ H-NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.02 (s, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.56 (d, J = 7.6 Hz) , 1H), 7.40 (d, J = 7.5 Hz, 1H), 4.76 to 4.67 (m, 3H), 4.49 (d, J = 12.0 Hz, 1H), 4.34. ~ 4.22 (m, 3H).

Step 3: N-(((S) -3- (3-Fluoro-4- (6-(((S) -2-nitro-6,7-dihydro-5H-imidazo- [2,1-b] [1,3] -Oxazin-6-yloxy) methyl) pyridin-2-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide. The title compound is (6S) -6-[(6-bromopyridin-2-yl) methoxy] -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine Was used in place of 2-((5-bromopyrimidin-2-yloxy) methyl) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole. Prepared by following the same procedure as described for the preparation of Step 2. APCI MS m / z 527.4 (M + H). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.27 (t, J = 5.8 Hz, 1H), 8.05 (s, 1H), 7.98 (t, J = 8.9 Hz, 1H), 7.89 (t, J = 7.8 Hz, 1H), 7.70 (brd, J = 6.8 Hz, 1H), 7.62 (dd, J = 14.1, 2.2 Hz, 1H), 7.46 (dd, J = 8.8, 2.2 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 4.83 (d, J = 13.6 Hz, 1H) ), 4.80 (d, J = 13.6 Hz, 1H), 4.80-4.75 (m, 1H), 4.74 (dt, J = 12.0, 2.5 Hz, 1H), 4 .51 (d, J = 11.9 Hz, 1H), 4.40 to 4.33 (m, 2H), 4.26 (dd, J = 13.9, 3.6 Hz, 1H), 4.18 ( t, J = 9.0 Hz, 1H), 3.80 (dd, J = 9.2, 6.5 Hz, 1H), 3.44 (t, J = 5.5 Hz, 2H), 1.84 (s, 3H).
Example 56

  N-(((S) -3- (3-Fluoro-4- (6-(((S) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 ] -Oxazin-6-yloxy) methyl) pyridazin-3-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide:

Step 1: (6S) -6-[(6-Chloro-3-pyridazinyl) methoxy] -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. Sodium hydride (60% w / w, 0.30 g, 7.6 mmol) was added to (6S) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] in DMF (20 mL). To a solution of [1,3] oxazin-6-ol (0.89 g, 4.8 mmol) was added at 0 ° C. The resulting solution was cooled to −42 ° C. and a solution of 3- (bromomethyl) -6-chloropyridazine (1.05 g, 5.1 mmol) in DMF (5 mL) was added. The mixture was stirred at −42 ° C. for 1 hour and then quenched with ice. EtOAc (200 mL) was added and the organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting first with hexane / EtOAc (1: 1) to remove unreacted 3- (bromomethyl) -6-chloropyridazine and then with EtOAc. To give the title compound (0.84 g, 56%) as a white solid. APCI MS m / z 312.6 (M + H). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.02 (s, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 4.97 (d, J = 13.2 Hz, 1H), 4.94 (d, J = 13.2 Hz, 1H), 4.69 (dt, J = 12.0, 2.6 Hz, 1H) ), 4.50 (d, J = 12.1 Hz, 1H), 4.30 to 4.39 (m, 2H), 4.25 (dd, J = 13.5, 3.3 Hz, 1H).

Step 2: N-(((S) -3- (3-Fluoro-4- (6-(((S) -2-nitro-6,7-dihydro-5H-imidazo- [2,1-b] [1,3] -Oxazin-6-yloxy) methyl) pyridazin-3-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) -acetamide. The title compound is (6S) -6-[(6-chloro-3-pyridazinyl) methoxy] -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. Example 51, except that 2-((5-bromopyrimidin-2-yloxy) methyl) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole was used. Prepared by following the same procedure as described for the preparation of Step 2. APCI MS m / z 528.3 (M + H). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.23 (t, J = 5.8 Hz, 1H), 8.09 to 8.02 (m, 2H), 8.03 (s, 1H) 7.75 (d, J = 8.8 Hz, 1H), 7.68 (dd, J = 14.0, 2.2 Hz, 1H), 7.52 (dd, J = 8.7, 2.2 Hz) , 1H), 5.04 (d, J = 13.6 Hz, 1H), 5.00 (d, J = 13.6 Hz, 1H), 4.83 to 4.75 (m, 1H), 4.74. (Dt, J = 12.0, 2.5 Hz, 1H), 4.52 (d, J = 11.9 Hz, 1H), 4.43 to 4.34 (m, 2H), 4.28 (dd, J = 13.5, 3.2 Hz, 1H), 4.20 (t, J = 9.0 Hz, 1H), 3.82 (dd, J = 9.2, 6.4 Hz, 1H), 3.45 (T, J = .5Hz, 2H), 1.84 (s, 3H).
Example 57

  N-(((S) -3- (3-Fluoro-4- (5-(((S) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 ] -Oxazin-6-yloxy) methyl) pyrazin-2-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide:

Step 1: (6S) -6-[(5-Chloro-2-pyrazinyl) methoxy] -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. Triethylamine (4.17 mL, 3.0 mmol) and mesyl chloride (1.57 mL, 2.00 mmol) were added to (5-chloro-2-pyrazinyl) methanol (1.44 g, 10.0 mmol) in anhydrous THF (20 mL). To the solution at 0 ° C. The mixture was stirred at 0 ° C. for 0.5 h and then partitioned between EtOAc / water. The organic fraction was dried (MgSO ₄ ) and the solvent was removed under reduced pressure to give the crude mesylate. The mesylate was dissolved in acetone (40 mL), sodium iodide (7.5 g, 50 mmol) was added and the mixture was refluxed for 1 hour. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc / water. The residue was chromatographed on silica gel (DCM) to give 2-chloro-5- (iodomethyl) pyrazine. Sodium hydride (60% w / w, 0.36 g, 9.0 mmol) was added to (S) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] in DMF (10 mL). To a solution of [1,3] oxazin-6-ol (0.93 g, 5.02 mmol) and 2-chloro-5- (iodomethyl) pyrazine (1.54 g, 6.05 mmol) was added at −78 ° C. . The mixture was stirred at 0 ° C. for 1 hour and then quenched with ice. EtOAc (200 mL) was added and the organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with a gradient (0-5%) of MeOH / EtOAc to give the title compound (1.015 g, 65%) as a white solid. APCI MS m / z 312.6 (M + H). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.76 (d, J = 1.4 Hz, 1H), 8.50 (d, J = 1.4 Hz, 1H), 8.02 (s, 1H), 4.85 (d, J = 13.7 Hz, 1H), 4.81 (d, J = 13.7 Hz, 1H), 4.70 (td, J = 12.1, 2.6 Hz, 1H) ), 4.49 (bd, J = 12.0 Hz, 1H), 4.29-4.38 (m, 2H), 4.25 (dd, J = 13.5, 3.3 Hz, 1H).

Step 2: N-(((S) -3- (3-Fluoro-4- (5-(((S) -2-nitro-6,7-dihydro-5H-imidazo- [2,1-b] [1,3] -Oxazin-6-yloxy) methyl) pyrazin-2-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide. The title compound is (6S) -6-[(5-chloro-2-pyrazinyl) methoxy] -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. Example 51, except that 2-((5-bromopyrimidin-2-yloxy) methyl) -2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] oxazole was used. Prepared by following the same procedure as described for the preparation of Step 2. APCI MS m / z 528.3 (M + H). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.98 (dd, J = 2.1, 1.7 Hz, 1H), 8.76 (d, J = 1.4 Hz, 1H), 8. 22 (t, J = 5.8 Hz, 1H), 8.04 (s, 1H), 8.02 (t, J = 8.8 Hz, 1H), 7.67 (dd, J = 14.0, 2 .2 Hz, 1H), 7.51 (dd, J = 8.8, 2.2 Hz, 1H), 4.89 (d, J = 13.4 Hz, 1H), 4.86 (d, J = 13. 4Hz, 1H), 4.82 to 4.75 (m, 1H), 4.74 (dt, J = 12.0, 2.5Hz, 1H), 4.52 (d, J = 12.0Hz, 1H) ), 4.43 to 4.32 (m, 2H), 4.27 (dd, J = 13.5, 3.2 Hz, 1H), 4.19 (t, J = 9.0 Hz, 1H), 3 .81 (d , J = 9.2,6.5Hz, 1H), 3.44 (t, J = 5.5Hz, 2H), 1.84 (s, 3H).
Example 58

  N-({(5S) -3- [3-fluoro-4- (2- {4-[(2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] [1,3 ] Oxazol-2-yl) methyl] -1-piperazinyl} -5-pyrimidinyl) phenyl] -2-oxo-1,3-oxazolidine-5-yl} methyl) acetamide:

Step 1. tert-Butyl 4- [5- (4-{(5S) -5-[(acetylamino) methyl] -2-oxo-1,3-oxazolidin-3-yl} -2-fluorophenyl) -2-pyrimidinyl ] -1-Piperazinecarboxylate. Tert-Butyl 4- (5-bromo-2-pyrimidinyl) -1-piperazinecarboxylate (57 mg, 0.165 mmol) in a mixture of toluene (5.0 mL) and ethanol (2.0 mL) (US2007 / 0149561 A1 ), N- {3- [3-Fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] 2-oxo-oxazolidine-5-ylmethyl} acetamide (75 mg, 1.98 mmol) (Chen, S. et al .: prepared as described by US Pat. No. 7,129,259 or Gravestot et al., WO 2004/078753), PdCl ₂ (Dppf) (7.0 mg, 0.08 mmol) and 2N _{a 2 CO 3 (1.0mL, 2.00mmol} ) in a mixture of nitrogen purged, then refluxed for 5 hours under a nitrogen atmosphere. The product was extracted with EtOAc and the extract was washed thoroughly with water before work-up and chromatography on silica. The prefraction was eluted with EtOAc, while the title product was eluted with MeOH / EtOAc (1:19) as a cream solid (69.4 mg, 81%), APCI MS m / z 515.5. (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 8.59 (d, J = 1.4 Hz, 2H), 8.22 (t, J = 5.8 Hz, 1H), 7.63-7. 57 (m, 2H), 7.40 (dd, J = 8.6, 2.1 Hz, 1H), 4.80 to 4.70 (m, 1H), 4.16 (t, J = 9.1 Hz) , 1H), 3.79-3.76 (m, 5H), 3.45-3.40 (m, 6H), 1.84 (s, 3H), 1.43 (s, 9H).

Step 2. N-[((5S) -3- {3-Fluoro-4- [2- (1-piperazinyl) -5-pyrimidinyl] phenyl} -2-oxo-1,3-oxazolidine-5-yl) methyl] acetamide . Tert-Butyl 4- [5- (4-{(5S) -5-[(acetylamino) methyl] -2-oxo-1,3-oxazolidine- in CH ₂ Cl ₂ (10 mL) and TFA (10 mL) A solution of 3-yl} -2-fluorophenyl) -2-pyrimidinyl] -1-piperazinecarboxylate (0.24 g, 0.47 mmol) was stirred at room temperature for 90 minutes and then concentrated to dryness under vacuum. The residue was partitioned between EtOAc and 1N NaOH and worked up of the organic solution to give the title compound as a tan powder (0.18 g, 94%), APCI MS m / z 415.5. (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) 8.55 (d, J = 1.4 Hz, 2H), 8.27 (t, J = 5.8 Hz, 1H), 7.63 to 7.57 (M, 2H), 7.39 (dd, J = 8.6, 2.1 Hz, 1H), 4.80 to 4.71 (m, 1H), 4.16 (t, J = 9.1 Hz, 1H), 3.77 (dd, J = 9.1, 6.5 Hz, 1H), 3.72 to 3.69 (m, 4H), 3.43 (t, J = 5.5 Hz, 2H), 2.75 to 2.72 (m, 4H), 1.83 (s, 3H).

Step 3. N-({(55) -3- [3-fluoro-4- (2- {4-[(2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] [1,3 ] Oxazol-2-yl) methyl] -1-piperazinyl} -5-pyrimidinyl) phenyl] -2-oxo-1,3-oxazolidine-5-yl} methyl) acetamide. 2-Bromo-1- (2-methyl-oxiranylmethyl) -4-nitro-1H-imidazole (42 mg, 0.16 mmol) and N-[((5S) -3- {3 in isopropanol (4 mL). A solution of -fluoro-4- [2- (1-piperazinyl) -5-pyrimidinyl] phenyl} -2-oxo-1,3-oxazolidine-5-yl) methyl] acetamide (69 mg, 0.17 mmol) was added for 16 hours. Refluxed. The solvent was removed under vacuum and the residue was thoroughly dried under high vacuum. The residue was dissolved in dry DMF (2 mL) and the solution was cooled to 5 ° C. NaH (60% dispersion in 16 mg mineral oil, 0.40 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 30 minutes. Water was added and the mixture was extracted with EtOAc, the extract was worked up and chromatographed on silica. The previous fraction was eluted with EtOAc, while MeOH / EtOAc (1:19) gave the title compound as a cream powder after trituration with MeOH (31 mg, 32%), APCI MS m / z 596 5 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) 8.5 (d, J = 1.4 Hz, 2H), 8.22 (t, J = 5.8 Hz, 1H), 8.12 (s , 1H), 7.61 to 7.56 (m, 2H), 7.39 (dd, J = 8.6, 2.1 Hz, 1H), 4.79 to 4.72 (m, 1H), 4 .28 (d, J = 10.7 Hz, 1H), 4.15 (t, J = 9.1 Hz, 1H), 4.10 (t, J = 10.7 Hz, 1H), 3.78 (dd, J = 9.3, 6.5 Hz, 1H), 3.73-3.58 (m, 4H), 3.43 ( , J = 5.4 Hz, 2H), 2.82 (d, J = 15.4 Hz, 1H), 2.77 (d, J = 15.4 Hz, 1H), 2.64 to 2.59 (m, 4H), 1.84 (s, 3H), 1.58 (s, 3H).
Example 59

  (S, S) -N- (3- {2,3′-difluoro-4 ′-{-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine -6-yloxymethyl) -biphenyl-4-yl] -2-oxo-oxazolidine-5-yl} methyl) acetamide:

Step 1.6 (S)-(4-Bromo-2-fluorobenzyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. 2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6 (S) -ol (1.40 g, 7.58 mmol) in anhydrous DMF (30 mL) and To a solution of 4-bromo-1- (bromomethyl) -2-fluorobenzene (2.66 g, 9.93 mmol) was added 60% NaH (427 mg, 10.70 mmol) at 0 ° C. under N ₂ followed by , quickly degassed, and sealed again under N _2. The mixture was slowly warmed to room temperature and stirred at room temperature for 3 hours. The reaction mixture was cooled (solid CO ₂ / acetone), quenched with ice / aqueous NaHCO ₃ (20 mL), added to brine (150 mL) and extracted with CH ₂ Cl ₂ (4 × 80 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-2% EtOAc / CH ₂ Cl ₂ initially gave the precursor, followed by elution with 3-5% EtOAc / CH ₂ Cl ₂ gave the title compound as a pale yellow Obtained as a solid (2.63 g, 93%); APCI MS m / z 372, 374 (bromine isotope pattern, M + H ⁺ ); ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 01 (s, 1H), 7.54 (dd, J = 9.7, 1.8 Hz, 1H), 7.42 (dd, J = 8.2, 1.8 Hz, 1H), 7.37 (dd , J = 8.1, 7.7 Hz, 1H), 4.72 to 4.62 (m, 3H), 4.47 (brd, J = 11.9 Hz, 1H), 4.30 to 4.19. (M, 3H).

Step 2. (S, S) -N- (3- {2,3′-difluoro-4 ′-{-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine -6-yloxy) biphenyl-4-yl] -2-oxooxazolidine-5-yl} methyl) acetamide: 6 (S)-(4 in toluene / EtOH (5/3, 4 mL) and DMF (4 mL). -Bromo-2-fluorobenzyloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine (100 mg, 0.26 mmol), N- {3- [ 3-Fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide (112 mg, 0.29mmo ), And 2M _K 2 _CO 3 (1mL, the degassed solution of 2.00 _mmol) was added PdCl 2 (dppf) (12mg, 0.05mmol). The mixture was heated to 100 ° C. under N _{2 for} 1 hour, diluted with water, extracted with EtOAc (3 × 50 mL) and concentrated in vacuo. The crude product was purified by flash chromatography on silica (0-5% MeOH / CH ₂ Cl ₂ ) to give the title product (75 mg, 52%). APCI MS m / z 544.4 (M + H ⁺ ); ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.22 (t, J = 5.7, 1H), 8.03 (s, 1H) 7.63-7.58 (m, 2H), 7.51 (t, J = 7.8 Hz, 1H), 7.43-7.38 (m, 3H), 4.80-4.67 ( m, 4H), 4.50 (d, J = 11.9 Hz, 1H), 4.33 to 4.24 (m, 3H), 4.17 (t, J = 9.1 Hz, 1H), 3. 79 (dd, J = 9.2, 6.5 Hz, 1H), 3.43 (t, J = 5.4 Hz, 2H), 1.84 (s, 3H).
Example 60

  N-[((5S) -3- {3-Fluoro-4- [5-({[(6S) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1, 3] Oxazin-6-yl] oxy} methyl) -2-thienyl] phenyl} -2-oxo-1,3-oxazolidine-5-yl) methyl] acetamide:

Step 1: (6S) -6-[(5-Bromo-2-thienyl) methoxy] -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. NaH (60% w / w, 0.60 g, 15 mmol) was added to (6S) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 in DMF (40 mL). ] Oxazin-6-ol (2.00 g, 10.8 mmol) and 2-bromo-5- (bromomethyl) thiophene (prepared by the method of Mamane et al., Synthesis 3; 2003; 455-467) (3.20 g, 12 .5 mmol) was added at 0 ° C. The mixture was stirred at 0 ° C. for 2 hours, then poured onto ice and extracted with EtOAc (2 × 200 mL). The organic layer was dried and evaporated. Column chromatography (hexane / EtOAc, gradient elution) gave the title compound (2.985 g, 77%) as a white solid. APCI MS m / z 360, 362 (M + H). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.00 (s, 1H), 7.11 (d, J = 3.7 Hz, 1H), 6.95 (d, J = 3.7 Hz, 1H) 4.79 (d, J = 13.2 Hz, 1H), 4.76 (d, J = 13.2 Hz, 1H), 4.60 (dt, J = 12.0, 1.6 Hz, 1H), 4.44 (d, J = 12.0 Hz, 1H), 4.19-4.25 (m, 3H).

Step 2: N-[((5S) -3- (3-Fluoro-4- [5-({[(6S) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yl] oxy} methyl) -2-thienyl] phenyl} -2-oxo-1,3-oxazolidine-5-yl) methyl] acetamide EtOH (3 mL), toluene (5 mL) , DMF (8 mL) and K ₂ CO ₃ (2 mL, 2M, 4 mmol) in (6S) -6-[(5-bromo-2-thienyl) methoxy] -2-nitro-6,7-dihydro-5H -Imidazo [2,1-b] [1,3] oxazine (0.200 g, 0.555 mmol) and N-({(5S) -3- [3-fluoro-4- (4,4,5,5) -Tetramethyl-1,3,2-dioxaborolane- A mixture of 2-yl) phenyl] -2-oxo-1,3-oxazolidine-5-yl} methyl) acetamide (0.252 g, 0.666 mmol) was purged with nitrogen: PdCl ₂ (dppf) (23 mg, 0.03 mmol) was added and the mixture was refluxed under nitrogen for 1 hour, then partitioned between EtOAc and water, column chromatography (9: 1 DCM / MeOH) yielded a solid, then This was reprecipitated with DCM / MeOH to give the title compound (0.142 g, 48%) as a light gray solid: APCI MS m / z 532 (M + H) ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.22 (t, J = 5.7 Hz, 1H), 8.02 (s, 1H), 7.76 (t, J = 8.9 Hz, 1H), 7.59 (d d, J = 14.0, 2.1 Hz, 1H), 7.36-7.43 (m, 2H), 7.13 (d, J = 3.3, 1H), 4.87 (d, J = 13.6 Hz, 1 H), 4.84 (d, J = 13.6 Hz, 1 H), 4.72 to 4.80 (m, 1 H), 4.64 (bd, J = 12.4 Hz, 1 H) 4.47 (d, J = 11.9 Hz, 1H), 4.21-4.30 (m, 3H), 4.15 (t, J = 9.1 Hz, 1H), 3.74-3. 81 (m, 1H), 3.43 (t, J = 5.4 Hz, 2H), 1.84 (s, 3H).
Example 61

  N-({(5S) -3- [3-fluoro-4- (6- {4-[(2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] [1,3 ] Oxazol-2-yl) methyl] -1-piperazinyl} -3-pyridinyl) phenyl] -2-oxo-1,3-oxazolidine-5-yl} methyl) acetamide:

Step 1: tert-Butyl 4- [5- (4-{(5S) -5-[(acetylamino) methyl] -2-oxo-1,3-oxazolidin-3-yl} -2-fluorophenyl)- 2-Pyridinyl] -1-piperazinecarboxylate. DMF (4mL), EtOH (1.5mL ), toluene (2.5 mL) and _{K 2 CO 3 (1mL, 2M} , 2mmol) in, tert- butyl 4- (5-bromo-2-pyridinyl) -1- Piperazine carboxylate (0.203 g, 0.593 mmol) and N-({(5S) -3- [3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- A mixture of 2-yl) phenyl] -2-oxo-1,3-oxazolidine-5-yl} methyl) acetamide (0.270 g, 0.714 mmol) was purged with nitrogen. PdCl ₂ (dppf) (24 mg, 0.03 mmol) was added and the mixture was heated at 90 ° C. under nitrogen for 1 h before being partitioned between EtOAc and water. Column chromatography (EtOAc) gave the title compound (0.210 g, 69%) as a white solid. APCI MS m / z 514 (M + H). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (bs, 1H), 8.27 (t, J = 5.9 Hz, 1H), 7.75 (ddd, J = 8.9, 2. 4, 1.7 Hz, 1 H), 7.53 to 7.60 (m, 2 H), 7.38 (dd, J = 8.6, 2.2 Hz, 1 H), 6.94 (d, J = 8 .9 Hz, 1 H), 4.72 to 4.79 (m, 1 H), 4.15 (t, J = 9.1 Hz, 1 H), 3.77 (dd, J = 9.2, 6.5 Hz, 1H), 3.52 to 3.57 (m, 4H), 3.40 to 3.46 (m, 6H), 1.84 (s, 3H), 1.43 (s, 9H).

Step 2: N-[((5S) -3- {3-Fluoro-4- [6- (1-piperazinyl) -3-pyridinyl] phenyl} -2-oxo-1,3-oxazolidine-5-yl) Methyl] acetamide. Tert-Butyl 4- [5- (4-{(5S) -5-[(acetylamino) methyl] -2-oxo-1,3-oxazolidine-3 in DCM (10 mL) and trifluoroacetic acid (10 mL) A solution of -yl} -2-fluorophenyl) -2-pyridinyl] -1-piperazinecarboxylate (0.191 g, 0.372 mmol) was stirred at room temperature for 3 hours. The solvent was removed under vacuum and the residue was partitioned between EtOAc and 1M NaOH solution. The organic layer was dried and evaporated to give the title compound (0.150 g, 98%) as a colorless foam. APCI MS m / z 414 (M + H). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (s, 1H), 8.22 (t, J = 5.8 Hz, 1H), 7.72 (bdt, J = 9.0, 2. 1 Hz, 1H), 7.52 to 7.60 (m, 2H), 7.38 (dd, J = 8.6, 2.1 Hz, 1H), 6.89 (d, J = 9.0 Hz, 1H) ) 4.72 to 4.80 (m, 1H), 4.16 (t, J = 9.0 Hz, 1H), 3.78 (dd, J = 9.1, 6.7 Hz, 1H), 3 .41-3.51 (m, 6H), 2.80-2.85 (m, 4H), 1.84 (s, 3H).

Step 3: N-({(5S) -3- [3-Fluoro-4- (6- {4-[(2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] [ 1,3] oxazol-2-yl) methyl] -1-piperazinyl} -3-pyridinyl) phenyl] -2-oxo-1,3-oxazolidine-5-yl} methyl) acetamide. N-[((5S) -3- {3-Fluoro-4- [6- (1-piperazinyl) -3-pyridinyl] phenyl} -2-oxo-1,3-oxazolidine- in ethoxyethanol (10 mL) 5-yl) methyl] acetamide (0.147 g, 0.355 mmol), 2-bromo-1-[(2-methyl-2-oxiranyl) methyl] -4-nitro-1H-imidazole (0.092 g, .0. 35 mmol) and diisopropylethylamine (70 μL, 0.40 mmol) were refluxed for 2.5 hours. The solution was evaporated onto silica gel and column chromatography (0-10% MeOH / EtOAc, gradient elution) gave a solid that was reprecipitated from refluxing MeOH to give the title compound (25 mg, 12%) as a cream Obtained as a colored solid. APCI MS m / z 595 (M + H). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.28 (bs, 1 H), 8.21 (t, J = 5.8 Hz, 1 H), 8.12 (s, 1 H), 7.70 (bdt , J = 9.0, 2.2 Hz, 1H), 7.51 to 7.59 (m, 2H), 7.37 (dd, J = 8.6, 2.2 Hz, 1H), 6.88 ( d, J = 9.0 Hz, 1H), 4.71 to 4.79 (m, 1H), 4.29 (d, J = 10.7 Hz, 1H), 4.15 (t, J = 9.0 Hz) , 1H), 4.09 (d, J = 10.7 Hz, 1H), 3.77 (dd, J = 9.2, 6.5 Hz, 1H), 3.31-3.47 (m, 6H) 2.82 (d, J = 14.7 Hz, 1H), 2.78 (d, J = 14.7 Hz, 1H), 2.72 to 2.79 (m, 4H), 1.84 (s, 3H), 1. 58 (s, 3H).
Example 62

  3- {3-Fluoro-4- [5- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl) -pyridine-2 -Yl] -phenyl} -5-hydroxymethyl-oxazolidine-2-one:

Step 1.5- (tert-Butyl-dimethyl-silanyloxymethyl) -3- {3-fluoro-4- [5- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b ] [1,3] Oxazin-6-yloxymethyl) -pyridin-2-yl] -phenyl} -oxazolidine-2-one: 6- (in DMF / H ₂ O (10 / 1.5.5 mL). 6-Bromo-pyridin-3-ylmethoxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine (150 mg, 0.40 mmol), 5- (tert- Butyl-dimethyl-silanyloxymethyl) -3- [3-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -oxazolidine- 2-on ( 98 mg, 0.44 _mmol), and degassed suspension of _{Pd (Ph 3 P) 4 (} 58mg, 0.05mmol) and _{K 2 CO 3 (121mg, 0.88mmol} ). The mixture was heated to 80 ° C. for 2.5 hours, diluted with EtOAc, washed with brine and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography (5% MeOH in EtOAc) to give the title product (170 mg). ESI MS m / z 600.5 (M + H ^< + ^> ).

Step 2. 3- {3-Fluoro-4- [5- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl)- Pyridin-2-yl] -phenyl} -5-hydroxymethyl-oxazolidine-2-one: 5- (tert-butyl-dimethyl-silanyloxymethyl) -3- {3-fluoro in THF (8.0 mL) -4- [5- (2-Nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl) -pyridin-2-yl] -phenyl} To a solution of -oxazolidin-2-one (170 mg) was added TBAF (1.0 mL, 1.0 mmol, 1.0 M in THF). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with brine and purified by flash chromatography to give the title product (89 mg) as a yellow solid. ESI MS m / z 486.4 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 8.63 (d, J = 1.6 Hz, 1H), 8.03 (s, 1H), 7.99 ( t, J = 9.0 Hz, 1H), 7.81 (dd, J = 8.4, 2.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.63 (dd , J = 14.8, 2.8 Hz, 1H), 7.46 (dd, J = 8.8, 1.6 Hz, 1H), 5.24 (t, J = 5.6 Hz, 1H), 4. 74 to 4.66 (m, 3H), 4.46 (d, J = 12.0 Hz, 1H), 4.30 to 4.20 (m, 2H), 4.12 (t, J = 9.0 Hz) , 1H), 3.86 (dd, J = 9.2, 6.4 Hz, 1H), 3.79 to 3.64 (m, 1H), 3.58 to 3.52 (m, 1H), 3 .16 3.12 (m, 2H).
Example 63

  3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyridazin-3-yl ] -Phenyl} -5-hydroxymethyl-oxazolidine-2-one:

The title compound is 6- (6-chloro-pyridazin-3-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. Bromo-pyridin-3-ylmethoxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Described for the preparation of Example 62 except that it was used in place of oxazine. Prepared by following the same procedure as ESI MS m / z 473.4 (M + H ^< + ^> ). ¹ H NMR (400 MHz, DMSO) δ 8.07 (s, 1H), 7.98 (dd, J = 9.2, 1.6 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H) ), 7.67 (dd, J = 14.4, 2.4 Hz, 1H), 7.53 (dd, J = 8.8, 2.0 Hz, 1H), 7.39 (d, J = 9. 2 Hz, 1 H), 6.00 (s, 1 H), 5.24 (t, J = 5.4 Hz, 1 H), 4.83 to 4.73 (m, 3 H), 4.53 (s, 1 H) 4.14 (t, J = 9.2 Hz, 1H), 3.88 (dd, J = 8.8, 6.0 Hz, 1H), 3.72 to 3.66 (m, 1H), 3. 59-3.53 (m, 1H).
Example 64

  3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl) -pyridine-3 -Yl] -phenyl} -5-hydroxymethyl-oxazolidine-2-one:

The title compound is 6- (5-bromo-pyridin-2-ylmethoxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine. Bromo-pyridin-3-ylmethoxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Described for the preparation of Example 62 except that it was used in place of oxazine. Prepared by following the same procedure as ESI MS m / z 486.4 (M + H ^< + ^> ). ¹ H NMR (400 MHz, DMSO) δ 8.68 (s, 1H), 8.04 (s, 1H), 7.96 (dt, J = 8.8, 1.6 Hz, 1H), 7.65 ( dd, J = 13.6, 2.4 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.46 (dd, J = 8.4, 2.8 Hz, 2H), 5 .74 (s, 1H), 5.24 (t, J = 5.6 Hz, 1H), 4.77 to 4.69 (m, 3H), 4.48 (d, J = 12.0 Hz, 1H) 4.35 to 4.22 (m, 3H), 4.12 (t, J = 9.2 Hz, 1H), 3.86 (dd, J = 8.8, 5.6 Hz, 1H), 3. 70-3.65 (m, 1H), 3.58-3.52 (m, 1H), 3.16-3.12 (m, 1H).
Example 65

  N- (3- {3,5-difluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy)- Pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

6- (5-Bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1 in DMF / H 2 O (10 / 1.5.5 mL) , 3] oxazine (200 mg, 0.515 mmol), N- {3- [3,5-difluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl ) -Phenyl] -2-oxo-oxazolidin-5-ylmethyl} -acetamide (238 mg, 0.60 mmol) (Biswajit et al., WO2006038100 A1 and Gravestok et al., WO 2004/078753 A1), Pd (Ph ₃ P) ₄ (70 mg) And a suspension of K ₂ CO ₃ (150 mg) was degassed. The mixture was heated to 80 ° C. for 2 hours, diluted with EtOAc, washed with brine and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography (5% MeOH in EtOAc) to give the title product (117 mg, 43%). ESI MS m / z 531.5 (M + H ^< + ^> ). ¹ H NMR (400 MHz, DMSO) δ 8.30 (s, 1H), 8.28 (t, J = 6.0 Hz, 1H), 8.07 (s, 1H), 7.93 (s, 1H) 7.85 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 10.4 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 5.77 ( s, 1H), 4.80 to 4.68 (m, 3H), 4.48 to 4.40 (m, 2H), 4.14 (t, J = 9.4 Hz, 1H), 3.75 ( dd, J = 9.2, 6.4 Hz, 1H), 3.41 (t, J = 5.4 Hz, 2H), 1.82 (s, 3H).
Example 66

  3- {3-Fluoro-4- [2-methyl-6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyridine -3-yl] -phenyl} -5-hydroxymethyl-oxazolidine-2-one:

The title compound is 6- (5-bromo-6-methyl-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine 6 Example 1 except that-(6-bromo-pyridin-3-ylmethoxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine was used. Prepared by following the same procedure as described for the preparation of ESI MS m / z 486.4 (M + H ^< + ^> ).
Example 67

  3- {3,5-difluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyridine-3 -Yl] -phenyl} -5-hydroxymethyl-oxazolidine-2-one:

The title compound is 5 (R)-(tert-butyl-dimethyl-silanyloxymethyl) -3- [3,5-difluoro-4- (4,4,5,5-tetramethyl- [1,3, 2) Dioxaborolan-2-yl) -phenyl] -oxazolidine-2-one (Biswajit et al., WO2006038100 A1 and Gravestot et al., WO2004 / 078753 A1) 5 (R)-(tert-butyl-dimethyl-silanyloxymethyl) Except for use in place of -3- [3-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -oxazolidine-2-one Was prepared by following the same procedure as described for the preparation of Example 30. ESI MS m / z 490.3 (M + H ^< + ^> ).
Example 68

  5-hydroxymethyl-3- {4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyridine-3- Yl] -3-trifluoromethoxy-phenyl} -oxazolidine-2-one:

The title compound is 5 (R)-(tert-butyl-dimethyl-silanyloxymethyl) -3- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane-2- Yl) -3-trifluoromethoxy-phenyl] -oxazolidine-2-one (Biswajit et al., WO2006038100 A1 and Gravestok et al., WO2004 / 078753 A1) 5 (R)-(tert-butyl-dimethyl-silanyloxymethyl) Except for use in place of -3- [3-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -oxazolidine-2-one Was prepared by following the same procedure as described for the preparation of Example 30. ESI MS m / z 538.4 (M + H ^< + ^> ). ⁺ ). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.20 (d, J = 2.4 Hz, 1H), 7.75 (dd, J = 8.8, 2.4 Hz, 1H), 7.69 (s, 1H), 7.58 (dd, J = 8.0, 2.0 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.84 ( dd, J = 8.8, 1.2 Hz, 1H), 5.81-5.79 (m, 1H), 4.86-4.78 (m, 2H), 4.55 (dd, J = 12 0.0, 0.8 Hz, 1H), 4.42 (d, J = 2.8 Hz, 2H), 4.11 to 4.03 (m, 2H), 3.82 to 3.78 (m, 1H) .
Example 69

  5-hydroxymethyl-3- [6 '-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy)-[2,3'] Bipyridinyl-5-yl] -oxazolidine-2-one:

The title compound is 5 (R)-(tert-butyl-dimethyl-silanyloxymethyl) -3- [6- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane-2- Yl) -pyridin-3-yl] -oxazolidine-2-one (Biswajit et al., WO2006038100 A1 and Gravestok et al., WO2004 / 078753 A1) 5 (R)-(tert-butyl-dimethyl-silanyloxymethyl) -3 -[3-Fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -oxazolidin-2-one, except that it was used instead of Prepared by following the same procedure as described for the preparation of Example 30. ESI MS m / z 455.3 (M + H ^< + ^> ). ¹ H NMR (400 MHz, DMSO) δ 8.88 (d, J = 2.4 Hz, 1H), 8.81 (d, J = 2.4 Hz, 1H), 8.38 (dd, J = 8.8) , 2.8 Hz, 1H), 8.12 (dd, J = 8.8, 2.8 Hz, 1H), 8.06 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H) 6.97 (d, J = 8.0 Hz, 1H), 5.78 (brs, 1H), 5.25 (t, J = 5.8 Hz, 1H), 4.78 to 4.68 (m, 1H), 4.47 (dd, J = 14.4, 3.6 Hz, 2H), 4.40 (d, J = 13.6 Hz, 1H), 4.16 (t, J = 9.0 Hz, 1H) ), 3.90 (dd, J = 8.8, 6.4 Hz, 1H), 3.71 to 3.66 (m, 1H), 3.60 to 3.54 (m, 1H).
Example 70

  3- {4- [4-Dimethylamino-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyrimidine-5 Yl] -3-fluoro-phenyl} -5-hydroxymethyl-oxazolidine-2-one:

The title compound is [5-bromo-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyrimidin-4-yl] -Dimethyl-amine was used instead of 6- (6-Bromo-pyridin-3-ylmethoxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine Prepared by following the same procedure as described for the preparation of Example 62 except ESI MS m / z 516.3 (M + H ^< + ^> ).
Example 71

  N- [3- (3-Fluoro-4- {5-[(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-ylamino) -methyl ] -Pyridin-2-yl} -phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide:

Step 1. (6-Bromo-pyridin-3-ylmethyl)-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yl) -amine: CH ₂ Cl _To a stirred solution of 2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-ylamine (92 mg, 0.5 mmol) in ₂ and MeOH was added 6-bromo. -Pyridine-3-carbaldehyde (93 mg, 0.5 mmol) and acetic acid (0.01 mL) were added and stirred for 1 hour at room temperature. NaBH (OAc) ₃ (1.0 g) was added to the reaction mixture and stirred overnight at room temperature. The mixture was quenched with saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ . The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography (10% MeOH in CH ₂ Cl ₂ ) to give the title product (76 mg). ESI MS m / z 354.3 (M + H ^< + ^> ).

Step 2. N- [3- (3-Fluoro-4- {5-[(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-ylamino) -methyl ] - pyridin-2-yl} - phenyl) -2-oxo - oxazolidin-5-ylmethyl] - _{acetamide: DMF / H 2 O (10} / 1.5.5mL) solution of (6-bromo - pyridine-3 Ylmethyl)-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yl) -amine (65 mg), N- {3- [3-fluoro -4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide (70 mg) (Gravestok et al. , WO200 / 078753 _A1), was degassed suspension of _{Pd (Ph 3 P) 4 (} 30mg) and _K 2 _CO 3 (60mg). The mixture was heated to 80 ° C. for 2.5 hours, diluted with EtOAc, washed with brine and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography (5% MeOH in EtOAc) to give the title product (30 mg). ESI MS m / z 526.3 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO) δ 8.62 (d, J = 2.0 Hz, 1H), 8.27 (t, J = 5.8 Hz, 1H) ), 7.99 (t, J = 8.8 Hz, 1H), 7.81 (dd, J = 7.6, 2.0 Hz, 1H), 7.72 (d, J = 6.8 Hz, 1H) 7.59 (dd, J = 14.4, 2.0 Hz, 1H), 7.43 (dd, J = 8.8, 2.4 Hz, 1H), 4.77 to 4.72 (m, 1H) ), 4.45 to 4.40 (m, 1H), 4.18 to 4.11 (m, 2H), 3.99 (dd, J = 15.2, 3.2 Hz, 1H), 3.84 (D, J = 6.8 Hz, 1H), 3.77 (dd, J = 9.2, 6.0 Hz, 1H), 3.41 (t, J = 5.4 Hz, 2H), 3.28- 3. 4 (m, 1H), 2.92~2.89 (m, 1H), 1.81 (s, 3H).
Example 72

  N- [3- (3-Fluoro-4- {6-[(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-ylamino) -methyl ] -Pyridin-3-yl} -phenyl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide:

Step 1. (5-Bromo-pyridin-2-ylmethyl)-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yl) -amine: The title compound is 5-bromo-pyridine-2-carbaldehyde to (6-bromo-pyridin-3-ylmethyl)-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Prepared by following the same procedure as described for the preparation of Example 71 except that it was used instead of oxazin-6-yl) -amine. ESI MS m / z 354.1 (M + H ^< + ^> ).

Step 2. N- [3- (3-Fluoro-4- {6-[(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-ylamino) -methyl ] -Pyridin-3-yl} -phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide: The title compound is 5-bromo-pyridin-2-ylmethyl)-(2-nitro-6,7-dihydro The preparation of Example 71 is described except that -5H-imidazo [2,1-b] [1,3] oxazin-6-yl) -amine was used in place of 6-bromo-pyridine-3-carbaldehyde. Prepared by following the same procedure as ESI MS m / z 526.3 (M + H ^< + ^> ). ¹ H NMR (400 MHz, DMSO) δ 8.66 (brs, 1H), 8.27 (t, J = 5.8 Hz, 1H), 7.94 to 7.89 (m, 1H), 7.64 to 7.60 (m, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.59 (dd, J = 8.8, 2.4 Hz, 1H), 4.77 to 4.73 (M, 1H), 4.44 (d, J = 2.8 Hz, 1H), 4.19 to 4.11 (m, 2H), 4.04 (dd, J = 12.0, 4.0 Hz, 1H), 3.93 (d, J = 6.8 Hz, 1H), 3.77 (dd, J = 9.2, 6.4 Hz, 1H), 3.41 (t, J = 5.6 Hz, 2H) ) 2.92-2.89 (m, 1H), 1.81 (s, 3H).
Example 73

  5-hydroxymethyl-3- {4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl) -pyridine- 3-yl] -3-trifluoromethoxy-phenyl} -oxazolidine-2-one:

The title compound is 6- (5-bromo-pyridin-2-ylmethoxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine 6- (5- Bromo-pyridin-2-yloxy) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] The preparation of Example 68 is described except that it was used in place of oxazine. Prepared by following the same procedure as ESI MS m / z 552.3 (M + H ^< + ^> ). ¹ H NMR (400 MHz, DMSO) δ 8.60 (d, J = 2.0 Hz, 1H), 8.04 (s, 1H), 7.94 (brs, 1H), 7.89 (dd, J = 8.4, 2.4 Hz, 1 H), 7.61 (d, J = 8.4 Hz, 1 H), 7.53 (dd, J = 8.8, 2.4 Hz, 1 H), 7.46 (d , J = 8.0 Hz, 1H), 5.74 (s, 2H), 5.24 (t, J = 5.6 Hz, 1H), 4.79 to 4.70 (m, 2H), 4.50. (D, J = 12.0 Hz, 1H), 4.36 to 4.33 (m, 1H), 4.27 to 4.22 (dd, J = 14.0, 3.6 Hz, 1H), 4. 14 (t, J = 8.8 Hz, 1H), 3.88 (dd, J = 9.6, 6.4 Hz, 1H), 3.71 to 3.67 9 m, 1H), 3.59-3. 54 (m, 1 ).
Example 74

  3- [2-Fluoro-4 ′-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -biphenyl-4-yl] -5-hydroxy Methyl-oxazolidin-2-one:

Step 1: 2- (4-Bromo-phenyl) -2-methyl-oxirane was synthesized according to the scheme shown in FIG. 4′-bromoacetophenone (0.60 g, 3 mmol) and diiodomethane (1.6 g, 6 mmol) were dissolved in 12 mL dry THF. Methyl lithium (5.6 mL, 1.6 M in ether) was added via syringe at 0 ° C. for 10 minutes. The resulting clear yellow solution was stirred at 0 ° C. for 30 minutes and then warmed to room temperature. After stirring at room temperature for 1 hour, the reaction mixture was quenched with ice. The resulting mixture was extracted with EtOAc, washed with brine and dried over Na ₂ SO ₄ . After removal of the solvent, an almost pure product (0.62 g) was obtained as a yellow solid that was used directly in the next step without further purification. ESI MS m / z 213, 215 (M + H).

Step 2: 2- (4-Bromo-phenyl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole was synthesized according to the scheme shown in FIG. 2- (4-Bromo-phenyl) -2-methyl-oxirane (213 mg, 1 mmol), 2-bromo-5-nitroimidazole (191 mg, 1 mmol) and triethylamine (0.4 mL) in a sealed tube at 80 ° C. Stir for hours. Column chromatography (EtOAc / hexane, v / v, 1/1 to 3/1) gave 330 mg of a yellow solid. The solid was dissolved in 5 mL of DMF containing Cs ₂ CO ₃ (780 mg, 2.4 mmol). The resulting mixture was stirred at 50 ° C. for 24 hours and then partitioned between EtOAc / water (200 mL, 1/1, v / v). The organic layer was washed with brine and dried over Na ₂ SO ₄ . Column chromatography (EtOAc / hexane, v / v, 1/1 to 3/1) gave the title compound (178 mg, 55% yield over two steps) as a yellow solid. ESI MS m / z 324, 326 (M + H). ¹ H NMR (400 MHz, acetone-d ₆ ) δ 7.66 (s, 1H), 7.76 (s, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.41 (d , J = 8.2 Hz, 2H), 4.58 (d, J = 10.8 Hz, 1H), 4.47 (d, J = 10.8 Hz, 1H), 1.89 (s, 3H).

Step 3: 3- [2-Fluoro-4 ′-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -biphenyl-4-yl]- 5-Hydroxymethyl-oxazolidine-2-one was synthesized according to the scheme shown in FIG. To a dry round bottom flask was added 5- (tert-butyl-dimethyl-silanyloxymethyl) -3- [3-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2]. Dioxaborolan-2-yl) -phenyl] -oxazolidine-2-one (148 mg, 0.33 mmol), 2- (4-bromo-phenyl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2 , 1-b] oxazole (about 97 mg, 0.3 mmol, impure), Ph (PPh ₃ ) ₄ (60 mg, 0.06 mmol) and K ₂ CO ₃ (85 mg, 0.6 mmol) were added. The flask was flushed with nitrogen and 4 mL of degassed DMF / H ₂ O (10/1, v / v) was added. The resulting mixture was stirred at 80 ° C. for 2 h before being cooled and partitioned between 60 mL EtOAc / 60 mL water. The organic layer was washed with brine and dried over Na ₂ SO ₄ . Column chromatography (CH ₂ Cl ₂ / MeOH, v / v, 20: 1 to 10: 1) gave the impure, TBS protected title compound (ca. 22 mg) as a yellow solid. This intermediate was dissolved in 2 mL of THF and cooled to 0 ° C. TBAF (0.15 mL, 1M in THF) was added dropwise from a syringe. The resulting mixture was warmed and stirred at root temperature for 2 hours. The reaction was then quenched with 0.4 mL saturated aqueous NH ₄ Cl. After all solvent was removed in vacuo, preparative TLC (CH ₂ Cl ₂ / MeOH, v / v, 10: 1) gave the product (4 mg) as a yellow solid. ESI MS m / z 455 (M + H). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.61 (s, 1H), 7.48-7.52 (m, 3H), 7.41-7.46 (m, 2H), 7.34- 7.40 (m, 1H), 7.24-7.27 (m, 1H), 4.66-4.74 (m, 1H), 4.40 (s, 2H), 4.03 (t, J = 8.8 Hz, 1H), 3.96 (dd, J = 8.8, 6.8 Hz, 1H), 3.83 (dd, J = 12.8, 3.6 Hz, 1H), 3.65 (Dd, J = 12.8, 3.6 Hz, 1H), 1.96 (s, 3H).
Example 75

  N- {3- [2-fluoro-4 '-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -biphenyl-4-yl]- 2-Oxo-oxazolidine-5-ylmethyl} -acetamide:

The title compound is described in Example 74 except that 2- (4-bromo-phenyl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole was used instead. Prepared by using the same procedure as described. The title compound was prepared according to the scheme shown in FIG. The title compound was obtained as a pale solid (12 mg). ESI MS m / z 496 (M + H). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.71 (s, 1H), 7.50-7.58 (m, 3H), 7.44-7.50 (m, 2H), 7.36- 7.44 (m, 1H), 7.22 to 7.30 (m, 1H), 4.68 to 4.80 (m, 1H), 4.40 to 4.50 (m, 2H), 4. 09 (t, J = 8.8 Hz, 1H), 3.78 (dd, J = 9.6, 6.8 Hz, 1H), 3.44-3.58 (m, 2H), 1.95 (s , 3H), 1.92 (s, 3H).
Example 76

  N- (3- {3-Fluoro-4- [6- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -pyridin-3-yl ] -Phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

Step 1: 5-Bromo-2-isopropenyl-pyridine was prepared according to the scheme shown in FIG. In a closed round bottom flask, 2-iodo-5-bromopyridine (4.34 g, 15.3 mmol), isopropenylboronic acid pinacol ester (2.57 g, 15.3 mmol), PdCl ₂ (dppf) (1. 87 g, 2.3 mmol) and potassium phosphate (8.2 g, 38 mmol) were dissolved in 25 mL DME and 8 mL water. The resulting solution was stirred at 80 ° C. for 3 hours and then cooled to room temperature. After separation, the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na ₂ SO ₄ . After removal of the solvent, an almost pure product (ca. 3.0 g) was obtained as a yellow solid that was used directly in the next step without further purification. ESI MS m / z 198, 200 (M + H).

Step 2: 5-Bromo-2- (2-methyl-oxiranyl) -pyridine was prepared according to the scheme shown in FIG. To a solution of 5-bromo-2-isopropenyl-pyridine (850 mg, 4.3 mmol) in 20 mL CH ₂ Cl ₂ was added mCPBA (1.43 g, 6.4 mmol, 77% maximum purity) at 0 ° C. It was. The resulting mixture was slowly warmed to room temperature and kept stirring at room temperature for 1 hour before being quenched with saturated aqueous NaHCO ₃ . The phases were separated and the organic layer was washed with saturated aqueous NaHCO ₃ , water and brine. Column chromatography (EtOAc / Hexane, v / v, 1/2) gave almost pure title compound (280 mg, 34% yield over two steps) as a slightly yellow oil. ESI MS m / z 214, 216 (M + H).

Step 3: 2- (5-Bromo-pyridin-2-yl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole was prepared according to the scheme shown in FIG. . The title compound was the same procedure as described for Example 74, Step 2, except that 5-bromo-2- (2-methyl-oxiranyl) -pyridine and 2-chloro-5-nitroimidazole were used as starting materials. It was prepared by using. The title compound was obtained as an off-white solid (323 mg, 26% yield over two steps). ESI MS m / z 325, 327 (M + H). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 8.4, 2.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 4.84 (d, J = 10.8 Hz, 1H), 4.24 (d, J = 10.8 Hz, 1H), 1. 90 (s, 3H).

Step 4: N- (3- {3-Fluoro-4- [6- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -pyridine- 3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide was prepared according to the scheme shown in FIG. The title compound was already used except that 2- (5-bromo-pyridin-2-yl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole was used instead. Prepared by using the same procedure as described. The title compound was obtained as a brown solid (103 mg, 59% yield). ESI MS m / z 497 (M + H). ¹ H NMR (400 MHz, acetone-d ₆ ) δ 8.82 (s, 1H), 8.06-8.14 (m, 1H), 7.91 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.72 (dd, J = 14.0, 2.0 Hz, 1H), 7.59-7.69 (m, 1H), 7.50-7.58 (m, 1H), 7.47 (dd, J = 8.4, 2.0 Hz, 1H), 5.07 (d, J = 11.2 Hz, 1H), 4.81 to 4.92 (m, 1H), 4.61 (d, J = 11.2 Hz, 1H), 4.27 (t, J = 9.2 Hz, 1H), 3.94 (dd, J = 9.2, 6.4 Hz, 1H), 3 .52-3.69 (m, 2H), 1.92 (s, 3H), 1.16 (s, 3H).
Example 77

  N- [3- (3-Fluoro-4- {2- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -piperazine- 1-yl] -pyrimidin-5-yl} -phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide:

Step 1: 1- [4- (5-Bromo-pyrimidin-2-yl) -piperazin-1-yl] -3- (2-chloro-4-nitro-imidazol-1-yl) -2-methyl-propane -2-ol was prepared according to the scheme shown in FIG. In a round bottom flask, 5-bromo-2-piperazin-1-yl-pyrimidine (1.07 g, 4.4 mmol), 2-chloro-1- (2-methyl-oxiranylmethyl) -4-nitro- 1H-imidazole (0.87 g, 4.0 mmol) and 24 mL EtOH were added. The resulting reaction mixture was stirred at 50 ° C. for 24 hours. After cooling to room temperature, the solid was filtered and washed with EtOAc to give the title compound. The mother liquor was ground for further product. Without further purification, the title compound (1.38 g, 75% yield) was obtained as an off-white solid. ESI MS m / z 462 (M + H). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (s, 2H), 8.06 (s, 1H), 4.01 (s, 2H), 3.79 (b, 4H), 3.35 ( s, 1H), 2.57 to 2.80 (m, 4H), 2.53 (d, J = 14.0 Hz, 1H), 2.37 (d, J = 14.0 Hz, 1H), 1. 16 (s, 3H).

Step 2: 2- [4- (5-Bromo-pyrimidin-2-yl) -piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole Was prepared according to the scheme shown in FIG. The product from Step 1 (1.38 g, 3.02 mmol) was dissolved in 20 mL DMF containing Cs ₂ CO ₃ (1.96 g, 6.04 mmol). The resulting mixture was stirred at 50 ° C. for 28 hours and then partitioned between EtOAc / water (200 mL, 1/1, v / v). The organic layer was washed with brine and dried over Na ₂ SO ₄ . Column chromatography (MeOH / dichloromethane, v / v, 1/10) gave the title compound (1.05 g, 93% recovery) as a pale solid. ESI MS m / z 424, 426 (M + H). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25 (s, 2H), 7.55 (s, 1H), 4.35 (d, J = 9.6 Hz, 1H), 3.95 (d, J = 9.6 Hz, 1H), 3.54 to 3.73 (m, 4H), 2.88 (d, J = 14.8 Hz, 1H), 2.53 to 2.77 (m, 4H), 2 .60 (d, J = 14.8 Hz, 1H), 1.63 (s, 3H).

Step 3: N- [3- (3-Fluoro-4- {2- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -Piperazin-1-yl] -pyrimidin-5-yl} -phenyl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide was prepared according to the scheme shown in FIG. The title compound is 2- [4- (5-bromo-pyrimidin-2-yl) -piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] Prepared using the same procedure as previously described except that oxazole was used as the starting material. The title compound was obtained as a brown solid (680 mg, 66% yield). ESI MS m / z 596 (M + H). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.40 (s, 2H), 7.83 to 7.92 (m, 1H), 7.59 (s, 1H), 7.40 to 7.52 ( m, 1H), 7.25 to 7.36 (m, 1H), 7.17 to 7.25 (m, 1H), 4.68 to 4.80 (m, 1H), 4.31 (d, J = 10.0 Hz, 1H), 3.42 to 3.80 (m, 8H), 2.78 to 2.95 (m, 2H), 2.45 to 2.76 (m, 5H), 93 (s, 3H), 1.58 (s, 3H).
Example 78

  3- (3-Fluoro-4- {2- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -piperazin-1-yl ] -Pyrimidin-5-yl} -phenyl) -5-hydroxymethyl-oxazolidine-2-one:

The title compound is 5- (tert-butyl-dimethyl-silanyloxymethyl) -3- [3-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane-2. -Il) -phenyl] -oxazolidine-2-one was used as the Suzuki coupling reactant and TBAF deprotection was required (see Example 2-1). Prepared using (see Example 77). The title compound was obtained as a yellow solid (103 mg, 52% yield). ESI MS m / z 555 (M + H). ¹ H NMR (DMSO-d ₆ ) δ 8.53 (s, 2H), 8.13 (s, 1H), 7.50-7.66 (m, 2H), 7.30-7.50 (m , 2H), 5.24 (t, J = 5.2 Hz, 1H), 4.66 to 4.77 (m, 1H), 4.26 (d, J = 10.8 Hz, 1H), 4.00. ˜4.16 (m, 2H), 3.84 (dd, J = 8.0, 6.8 Hz, 1H), 3.48 to 3.74 (m, 5H), 2.77 (s, 2H) , 2.59 (s, 4H), 1.55 (s, 3H).
Example 79

  3- {3-Fluoro-4- [6- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -pyridin-3-yl] -phenyl } -5-hydroxymethyl-oxazolidine-2-one:

The title compound is 5- (tert-butyl-dimethyl-silanyloxymethyl) -3- [3-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane-2. -Yl) -phenyl] -oxazolidine-2-one, and 2- (5-bromo-pyridin-2-yl) -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] Prepared using the same procedure as previously described except that oxazole was used as starting material and TBAF deprotection was required (see Example 2-1, Step 3). The title compound was obtained as a slightly yellow solid (60 mg). ESI MS m / z 456 (M + H). ¹ H NMR (DMSO-d ₆ ) δ 8.79 (s, 1H), 8.14 (s, 1H), 8.05 to 8.12 (m, 1H), 7.75 (d, J = 8 .8 Hz, 1H), 7.63 (dd, J = 5.2, 2.8 Hz, 1H), 7.48 (dd, J = 8.8, 2.0 Hz, 1H), 5.24 (t, J = 5.6 Hz, 1H), 4.85 (d, J = 10.8 Hz, 1H), 4.69 to 4.77 (m, 1H), 4.49 (d, J = 10.8 Hz, 1H) ), 4.12 (t, J = 8.8 Hz, 1H), 3.86 (dd, J = 8.8, 5.6 Hz, 1H), 3.64 to 3.72 (m, 1H), 3 .50-3.59 (m, 1H), 1.97 (s, 3H).
Example 80

  N- (3- {2-fluoro-4 ′-[4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -piperazine-1- Yl] -biphenyl-4-yl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide:

The title compound was prepared using the same procedure as previously described except that 1- (4-bromo-phenyl) -piperazine was used as the starting material in Step 1 (see Example 77). The title compound was obtained as a slightly yellow solid (130 mg in final step, 60% yield). ESI MS m / z 594 (M + H). ¹ H NMR (DMSO-d ₆ ) δ 8.25 (t, J = 4.4 Hz, 1H), 8.12 (s, 1H), 7.44-7.56 (m, 3H), 7.29 7.39 (m, 3H), 6.94 (d, J = 8.4 Hz, 1H), 4.68-4.77 (m, 1H), 4.25 (d, J = 10.8 Hz, 1H), 4.11 (t, J = 8.8 Hz, 1H), 4.06 (d, J = 10.8 Hz, 1H), 3.74 (dd, J = 8.8, 6.8 Hz, 1H) ), 3.36 to 3.43 (m, 2H), 2.94 to 3.12 (m, 4H), 2.61 to 2.70 (m, 4H), 1.81 (s, 3H), 1.55 (s, 3H).
Example 81

  N- [3- (3-Fluoro-4- {6- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -piperazine- 1-yl] -pyridin-3-yl} -phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide:

The title compound was prepared using the same procedure as previously described except that 1- (5-bromo-pyridin-2-yl) -piperazine was used as the starting material in Step 1 (see Example 77). ). The title compound was obtained as a brown solid (196 mg in final step, 75% yield). ESI MS m / z 595 (M + H). ¹ H NMR (DMSO-d ₆ ) δ 8.25 (s, 1H), 8.12 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.44-7.58 (M, 3H), 7.34 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.68 to 4.77 (m, 1H), 4 .26 (d, J = 10.8 Hz, 1H), 4.04 to 4.17 (m, 3H), 3.74 (dd, J = 8.4, 6.4 Hz, 1H), 3.36 to 3.45 (m, 3H), 3.14 (dd, J = 5.6, 1.6 Hz, 1H), 2.61 (s, 2H), 2.48 (m, 4H), 1.81 ( s, 3H), 1.55 (s, 3H).
Example 82

  Phosphoric acid mono- (3- {3-fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy)- Pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) ester:

Step 1: Phosphoric acid di-tert-butyl ester 3- {3-fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine -6-yloxy) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidin-5-ylmethyl ester was prepared according to the scheme shown in FIG. 3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) in a round bottom flask -Pyridin-3-yl] -phenyl} -5-hydroxymethyl-oxazolidine-2-one (53 mg, 0.1 mmol), diphospho-phosphoramidic acid di-tert-butyl ester (0.078 mL, 0. 3 mmol), tetrazole (0.68 mL, about 0.31 mmol, about 0.45 M in MeCN), 15 mL dry THF and 2 mL dry dichloromethane were added. The resulting reaction mixture was stirred at room temperature for 16 hours and then cooled to -78 ° C. mCPBA (34 mg, 0.15 mmol) was added and the resulting solution was stirred at −78 ° C. for 2 hours. It was then warmed to room temperature, diluted with 100 mL EtOAc, washed with saturated aqueous NaHCO ₃ (2 × 100 mL), brine, and dried over Na ₂ SO ₄ . Preparative TLC (CH ₂ Cl ₂ / MeOH, v / v, 10: 1) gave the title compound (46 mg, 70% yield) as a white solid. ESI MS m / z 664 (M + H). ¹ H NMR (CDCl ₃ ) δ 8.29 (s, 1H), 7.79-7.84 (m, 1H), 7.58 (dd, J = 12.8, 2.0 Hz, 1H), 7 .45 (s, 1H), 7.39 (t, J = 8.8 Hz, 1H), 7.33 (dd, J = 8.8, 2.4 Hz, 1H), 6.86 (d, J = (8.8 Hz, 1H), 5.77 to 5.82 (m, 1H), 4.84 to 4.92 (m, 1H), 4.84 (dd, J = 12.4, 2.8 Hz, 1H) ), 4.55 (dd, J = 12.4, 1.6 Hz, 1H), 4.41 (d, J = 2.8 Hz, 2H), 4.04 to 4.27 (m, 4H), 1 .49 (s, 9H), 1.45 (s, 9H).

Step 2: Phosphoric acid mono- (3- {3-fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 (Iloxy) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) ester was prepared according to the scheme shown in FIG. Di-tert-butyl phosphate 3- {3-fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 (Iloxy) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidin-5-ylmethyl ester (13 mg) was dissolved in 1 mL of TFA / CH ₂ Cl ₂ (v / v, 1/2). The resulting solution was stirred at room temperature for 1 hour, after which all solvent was removed. The residue was washed successively with 3 mL CH ₂ Cl ₂ , 3 mL EtOAc and 3 mL MeOH. The residue was dried under vacuum to give the title compound (8 mg) as a white solid. ESI MS m / z 552 (M + H).
Example 83

  3- [3-Fluoro-4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yl) -phenyl] -5-hydroxymethyl- Oxazolidin-2-one:

  The title compound was synthesized according to the scheme shown in FIG. Step 1.2- {4- [5- (tert-Butyl-dimethyl-silanyloxymethyl) -2-oxo-oxazolidine-3-yl] -2-fluoro-phenyl} -acrylic acid ethyl ester:

5- (tert-Butyl-dimethyl-silanyloxymethyl) -3- [3-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl)- Phenyl] -oxazolidin-2-one (3.553 g, 7.879 mmol), 2-bromo-acrylic acid ethyl ester (1 g, 6.06 mmol), Pd (PPh ₃ ) ₄ (1 g, 0.909 mmol) and K ₂ To a mixture of CO ₃ (6.4 g, 12.12 mmol) was added anhydrous DMF / H ₂ O (10: 1, 66 mL total). The mixture was degassed under N ₂ atmosphere by evaporating under vacuum at −78 ° C. and warming to room temperature under N ₂ three times. The degassed mixture was stirred for 2 hours at 60 ° C., cooled to room temperature, quenched with water, diluted with EtOAc, washed with brine and water. The organic layer was separated, dried (MgSO ₄ ) and concentrated. Column chromatography gave 810 mg (56%) of product as a yellow oil. ESI MS m / z 410 (M + H ^< + ^> ).

  Step 2. 3- (2-Bromo-4-nitro-imidazol-1-yl) -2- {4- [5- (tert-butyl-dimethyl-silanyloxymethyl) -2-oxo-oxazolidine-3- Yl] -2-fluoro-phenyl} -propionic acid ethyl ester:

A solution of 2-bromo-4-nitro-1H-imidazole (1.9 g, 9.9 mmol) and Et ₃ N (483 μl, 3.465 mmol) in 1,4-dioxane (10 mL) was stirred at room temperature for 1 hour. (The solution turned from an opaque solution to a clear solution), then 2- {4- [5- (tert-butyl-dimethyl-silanyloxymethyl)-in 1,4-dioxane (10 mL)- A solution of 2-oxo-oxazolidin-3-yl] -2-fluoro-phenyl} -acrylic acid ethyl ester (810 mg, 1.98 mmol) was added. The mixture was stirred overnight (19 hours) at 80 ° C., cooled to room temperature and concentrated. The concentrated material was loaded directly onto the column (25% EtOAc / hexanes → 2% MeOH / CH ₂ Cl ₂ ) to give 996 mg (84%) of product as a yellow oil. ESI MS m / z 602 (M + H ^< + ^> ).

  Step 3. 3- {4- [2- (2-Bromo-4-nitro-imidazol-1-yl) -1-hydroxymethyl-ethyl] -3-fluoro-phenyl} -5- (tert-butyl-dimethyl -Silanyloxymethyl) -oxazolidine-2-one:

3- (2-Bromo-4-nitro-imidazol-1-yl) -2- {4- [5 in THF / H ₂ O / MeOH (3: 0.1, total 3.1 mL, 0.05 M). To a solution of-(tert-butyl-dimethyl-silanyloxymethyl) -2-oxo-oxazolidine-3-yl] -2-fluoro-phenyl} -propionic acid ethyl ester (100 mg, 0.166 mmol) was added H ₂ O. NaBH ₄ (19 mg, 0.498 mmol) in (1 mL) was added at room temperature. The reaction mixture was stirred for 40 minutes at room temperature, diluted with EtOAc, and quenched with saturated aqueous NH ₄ Cl at 0 ° C. The organic layer was separated and the aqueous layer was extracted with EtOAc and washed with brine and water. The organic layers were combined, dried (MgSO ₄ ) and concentrated. The column (50% EtOAc / hexane) gave 41 mg of product as a colorless oil. ESI MS m / z 574 (M + H ^< + ^> ).

  Step 4.5- (tert-Butyl-dimethyl-silanyloxymethyl) -3- [3-fluoro-4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1 , 3] oxazin-6-yl) -phenyl] -oxazolidine-2-one:

3- {4- [2- (2-Bromo-4-nitro-imidazol-1-yl) -1-hydroxymethyl-ethyl] -3-fluoro-phenyl} -5- (tert-) in DMF (7 mL) Cs ₂ CO ₃ (358 mg, 1.099 mmol) was added to a solution of butyl-dimethyl-silanyloxymethyl) -oxazolidine-2-one (210 mg, 0.366 mmol) and stirred for 7 hours at 50 ° C. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine and water. The organic layer was separated, dried (MgSO ₄ ) and concentrated. The column (60% EtOAc / hexane) gave 130 mg of a pale yellow solid. ESI MS m / z 493 (M + H ^< + ^> ).

  Step 5. 3- [3-Fluoro-4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yl) -phenyl] -5 Hydroxymethyl-oxazolidin-2-one:

5- (tert-Butyl-dimethyl-silanyloxymethyl) -3- [3-fluoro-4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b in THF (4 mL) ] To the solution of [1,3] oxazin-6-yl) -phenyl] -oxazolidine-2-one (130 mg, 0.264 mmol), TBAF (270 μl, 0.269 mmol) was added at 0 ° C. for 20 minutes at the same temperature. Stir with. The reaction mixture was quenched with saturated aqueous NH ₄ Cl, diluted with EtOAc, washed with brine and water. The organic layer was separated, dried (MgSO ₄ ) and concentrated. The column (5% MeOH / CH ₂ Cl ₂ → MeOH) gave 35 mg of product as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d) δ 8.11 (s, 1H), 7.35 (m, 2H), 5.22 (t, J = 5.6 Hz, 1H), 4.69 (m, 1H), 4.02 (m, 2H), 4.31 (m, 2H), 4.06 (t, J = 9.0 Hz, 1H), 3.83 (m, 2H), 3.65 (m , 1H), 3.53 (m, 1H). ESI MS m / z 379 (M + H ^< + ^> ).
Example 84

  N- {3- [3-Fluoro-4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yl) -phenyl] -2- Oxo-oxazolidine-5-ylmethyl} -acetamide:

  The title compound was synthesized according to the scheme shown in FIG. Step 1.2- {4- [5- (Acetylamino-methyl) -2-oxo-oxazolidine-3-yl] -2-fluoro-phenyl} -acrylic acid ethyl ester:

N- {3- [3-Luolo-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -2-oxo-oxazolidine-5-ylmethyl } -Acetamide (1.0 g, 2.646 mmol), 2-bromo-acrylic acid ethyl ester (260 μl, 2.405 mmol), Pd (PPh ₃ ) ₄ (556 mg, 0.481 mmol) and K ₂ CO ₃ (2. To a mixture of 53 g, 4.81 mmol) was added anhydrous DMF / H ₂ O (10: 1, 26.4 mL total). The mixture was degassed under N ₂ atmosphere by evaporating under vacuum at −78 ° C. and warming to room temperature under N ₂ three times. The degassed mixture was stirred for 4.5 hours at 80 ° C., cooled to room temperature, quenched with water, diluted with EtOAc, washed with brine and water. The organic layer was separated, dried (MgSO ₄ ) and concentrated. Column chromatography gave 2.3 mg (96%) of product as a yellow oil. ESI MS m / z 337 (M + H ^< + ^> ).

  Step 2.2- {4- [5- (Acetylamino-methyl) -2-oxo-oxazolidine-3-yl] -2-fluoro-phenyl} -3- (2-bromo-4-nitro-imidazole-1 -Yl) -propionic acid ethyl ester:

A solution of 2-bromo-4-nitro-1H-imidazole (2.54 g, 13.2 mmol) and Et ₃ N (645 μl, 4.62 mmol) in 1,4-dioxane (15 mL) was stirred for 1 hour at room temperature. (The solution turned from an opaque solution to a clear solution) and then 2- {4- [5- (acetylamino-methyl) -2-oxo-oxazolidine- in 1,4-dioxane (11 mL). A solution of 3-yl] -2-fluoro-phenyl} -acrylic acid ethyl ester (2.6 mmol) was added. The mixture was stirred for 3 days (71 hours) at 80 ° C., cooled to room temperature and concentrated. The concentrated material was applied directly to the next step. ESI MS m / z 530 (M + H ⁺ ), bromine pattern.

  Step 3. N- (3- {4- [2- (2-Bromo-4-nitro-imidazol-1-yl) -1-hydroxymethyl-ethyl] -3-fluoro-phenyl} -2-oxo-oxazolidine-5 Ylmethyl) -acetamide:

2- {4- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenyl} -3- (2-bromo in EtOH (2 mL total, 0.04 M) To a solution of -4-nitro-imidazol-1-yl) -propionic acid ethyl ester (42 mg, 0.08 mmol), NaBH ₄ (15 mg, 0.398 mmol) was added at 0-5 ° C. The reaction mixture was stirred for 2 h 30 min at 0-5 ° C., quenched with saturated aqueous NaHCO ₃ , diluted with EtOAc and H ₂ O and concentrated. The crude material was directly subjected to the next step. The product was confirmed by LCMS. ESI MS m / z 501 (M + H ^< + ^> ).

  Step 4. N- {3- [3-Fluoro-4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yl) -phenyl] -2- Oxo-oxazolidine-5-ylmethyl} -acetamide:

Crude N- (3- {4- [2- (2-bromo-4-nitro-imidazol-1-yl) -1-hydroxymethyl-ethyl] -3-fluoro-phenyl} -2 in DMF (1 mL) - oxo - oxazolidin-5-ylmethyl) - acetamide (9 mg, to a solution of _{0.018mmol), Cs 2 CO 3 (} 18mg, 0.054mmol) was added at room temperature and stirred for 4 hours at 50 ° C.. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine and water. The organic layer was separated, dried (MgSO ₄ ) and concentrated. Preparative TLC (5% MeOH / CH ₂ Cl ₂ ) gave 690 μg of a pale yellow solid. ESI MS m / z 420 (M + H ^< + ^> ).
Example 85

  2-allyl-2- (4-bromo-phenyl) -6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole:

  The title compound was synthesized according to the scheme shown in FIG. Step 1.1- (4-Bromo-phenyl) -2- (2-chloro-4-nitro-imidazol-1-yl) -ethanone:

2,4′-Dibromoacetophenone (5 g, 18 mmol), 2-chloro-4-nitro-1H-imidazole (4 g, 27 mmol, 1.5 eq) and K ₂ CO ₃ (3. ₃ ) in CH ₃ CN (180 mL). 73 g, 27 mmol, 1.5 eq) was stirred at 60 ° C. for 2 hours. The reaction mixture was cooled to room temperature and the solid precipitate was filtered. The precipitate was washed with water and the filtered mixture of organic solvent and water was separated. The organic layer was concentrated and recrystallized with acetone to give 5.5 g (15.99 mmol, 89%) of a brown solid. ESI MS m / z 346 (M + H ⁺ ), bromine double line pattern.

  Step 2.2- (4-Bromo-phenyl) -1- (2-chloro-4-nitro-imidazol-1-yl) -pent-4-en-2-ol:

To a solution of In (669 mg, 5.814 mmol, 2.0 equiv) in anhydrous DMF (15 mL) was added allyl bromide (0.984 mL, 11.628 mmol, 4.0 equiv) and stirred at 50 ° C. for 1 hour. A green solution was obtained. To this mixture was added a solution of 1- (4-bromo-phenyl) -2- (2-chloro-4-nitro-imidazol-1-yl) -ethanone in anhydrous DMF (14 mL) under N 2 atmosphere. Stir at 50 ° C. for hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine and water. The organic layer was separated, dried (MgSO ₄ ) and concentrated to give a quantitative yield of the crude product. ESI MS m / z 388 (M + H ⁺ ), bromine double line pattern.

  Step 3. 2-Allyl-2- (4-bromo-phenyl) -6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole:

To a solution of crude 2- (4-bromo-phenyl) -1- (2-chloro-4-nitro-imidazol-1-yl) -pent-4-en-2-ol in DMF (48 mL) was added Cs _2. CO ₃ (2.84 g, 8.7 mmol) was added and stirred at 50 ° C. for 2 hours. The reaction mixture was cooled to room temperature, quenched with water, diluted with EtOAC, washed with brine and water. The organic layer was separated, dried (MgSO ₄ ) and concentrated. The concentrate was recrystallized with EuOAc to give 270 mg of white solid. ¹ H NMR (400 MHz, DMSO-d) δ 8.11 (s, 1H), 7.64 (m, 2H), 7.38 (m, 2H), 5.80 (m, 2H), 5.12 (M, 2H), 4.62 (d, J = 11.2 Hz, 1H), 4.01 (d, J = 11.2 Hz, 1H), 2.96 (m, 2H); ESI MS m / z 352 (M + H ⁺ ).
Example 86

  N- {3- [4 '-(2-allyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -2-fluoro-biphenyl-4-yl]- 2-Oxo-oxazolidine-5-ylmethyl} -acetamide:

The title compound was synthesized according to the reaction scheme shown in FIG. 2-allyl-2- (4-bromo-phenyl) -6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole (80 mg, 0.229 mmol), N- {3- [3-fluoro -4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide (104 mg, 0.274 mmol ), Pd (PPh ₃ ) ₄ (53 mg, 0.046 mmol) and K ₂ CO ₃ (240 mg, 0.458 mmol) were added anhydrous DMF / H ₂ O (4 mL / 0.4 mL, 4.4 mL total). N ₂ was added at the bottom. The reaction mixture was stirred for 2 hours at 80 ° C., cooled to room temperature, quenched with water, diluted with EtOAc, washed with brine and water. The organic layer was separated, dried (MgSO ₄ ) and concentrated. Column chromatography gave 63 mg of a yellow solid. ¹ H NMR (400 MHz, DMSO-d) δ 8.26 (t, J = 5.8 Hz, 1H), 7.60 (m, 2H), 7.41 (m, 2H), 5.61 (m, 1H), 5.16 (m, 2H), 4.74 (m, 1H), 4.65 (d, J = 11.2 Hz, 1H), 4.48 (d, J = 11.2 Hz, 1H) 4.15 (d, J = 9.0 Hz, 1H), 3.76 (m, 1H), 3.41 (d, J = 1.3 Hz, 2H), 3.02 (m, 2H); ESI MS m / z 522 (M + H ^< + ^> )
Example 87

  3- [4- (2-Allyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -phenyl] -5-hydroxymethyl-oxazolidin-2-one:

  The title compound was synthesized according to the scheme shown in FIG. Step 1. Butyric acid 3- {4- [1- (2-chloro-4-nitro-imidazol-1-ylmethyl) -1-hydroxy-but-3-enyl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl ester :

Butyric acid 3- [4- (2-bromo-acetyl) -phenyl] -2-oxo-oxazolidin-5-ylmethyl ester was prepared based on literature procedures (see Tetrahedron, 1989, 1323). Butyric acid 3- [4- (2-bromo-acetyl) -phenyl] -2-oxo-oxazolidin-5-ylmethyl ester (1.2 g, 3.125 mmol), 2-chloro- in CH ₃ CN (30 mL) A solution of 4-nitro-1H-imidazole (694 mg, 4.688 mmol, 1.5 eq) and K ₂ CO ₃ (650 mg, 4.688 mmol, 1.5 eq) was stirred at 60 ° C. for 2 hours. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NH ₄ Cl, diluted with EtOAc, washed with brine and water. The organic layer was separated, dried (MgSO ₄ ) and concentrated. The crude material was used directly in the next step to prepare the title compound. To a solution of In (719 mg, 6.25 mmol, 2.0 eq) in anhydrous DMF (20 mL) was added allyl bromide (1.06 mL, 12.5 mmol, 4.0 eq) and stirred at 50 ° C. for 1 h. A green solution was obtained. To this mixture was added crude butyric acid 3- {4- [2- (2-chloro-4-nitro-imidazol-1-yl) -acetyl] -phenyl} -2-oxo-oxazolidine-5 in DMF (10 mL). The ylmethyl ester solution was added and stirred at 50 ° C. for 3 1/2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine and water. The organic layer was separated, dried (MgSO ₄ ) and concentrated. Column chromatography (50% EtOAc / hexanes → EtOAc) gave 693 mg (45% over two steps) of a yellow oil. ESI MS m / z 493 (M + H ^< + ^> ).

  Step 2. Butyric acid 3- [4- (2-allyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -phenyl] -2-oxo-oxazolidine-5-ylmethyl ester :

3- {4- [1- (2-Chloro-4-nitro-imidazol-1-ylmethyl) -1-hydroxy-but-3-enyl] -phenyl} -2-oxo-oxazolidine butyrate in DMF (24 mL) to a solution of 5-yl methyl ester _{(693mg, 1.409mmol), Cs 2} CO 3 (1.38g, 4.226mmol) was added and stirred for 18 h at 50 ° C.. The reaction mixture was cooled to room temperature, quenched with water, diluted with EtOAC, washed with brine and water. The organic layer was separated, dried (MgSO4) and concentrated. ESI MS m / z 457 (M + H ^< + ^> ).

  Step 3. 3- [4- (2-Allyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -phenyl] -5-hydroxymethyl-oxazolidine-2- on:

3- [4- (2-Allyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole-2 butyric acid in MeOH / CH ₂ Cl ₂ (3: 1, total 2.7 mL) - yl) - phenyl] -2-oxo - oxazolidin-5-yl methyl ester (32 mg, to a solution of _{0.07mmol), K 2 CO 3 (} 15mg, 0.105mmol) was added, 1 hour 30 minutes, at room temperature Stir and quench with 10% aqueous AcOH, dilute with water and EtOAc, concentrate and extract with EtOAc. The concentrate was loaded on preparative TLC to give 2.2 mg of product.
Example 88

  3- (3-Fluoro-4- {2- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl)-[1,4] Diazepan-1-yl] -pyrimidin-5-yl} -phenyl) -5-hydroxymethyl-oxazolidine-2-one:

Step 1: 1- (5-Bromo-pyrimidin-2-yl)-[1,4] diazepan. A solution of 5-bromo-2-chloro-pyrimidine (1.0 g, 5.1 mmol), [1,4] diazepane (1.0 g, 10.2 mmol) in CH ₃ CN (5.0 mL) at 50 ° C. Stir for 3 hours. The solid and solution filters were washed with brine and concentrated in vacuo to give the title product (1.1 g, 85%) as a brown solid. ESI MS m / z 258 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (s, 2H), 3.77 (m, 4H), 2.97 (q, J = 10 Hz, 2H ), 2.81 (q, J = 15 Hz, 2H), 2.02 (s, 1H) 1.83 (qt, J = 15 Hz, 2H).

Step 2: 1- (2-Bromo-4-nitro-imidazol-1-yl) -3- [4- (5-bromo-pyrimidin-2-yl)-[1,4] diazepan-1-yl]- 2-Methyl-propan-2-ol. 1- (5-Bromo-pyrimidin-2-yl)-[1,4] diazepane (0.5 g, 1.9 mol) and 2-bromo-1- (2-methyl-oxiranyl) in EtOH (5 mL) A solution of methyl) -4-nitro-1H-imidazolemethane (0.5 g, 1.9 mmol) was stirred at 50 ° C. for 12 hours. Solvent was removed and purified by column chromatography to give the title compound (604 mg, 61% yield) as a brown solid. ESI MS m / z 394, 519 (M + H). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (s, 2H), 8.05 (s, 1H) 3.92 (q, J = 36 Hz, 2H), 3.79 (m, 4H), 2 .96 (q, J = 12 Hz, 2H), 2.81 (q, J = 15 Hz, 2H), 2.63 (d, J = 35 Hz, 2H), 2.45 (d, J = 35 Hz, 2H) 1.85 (qt, J = 15 Hz, 2H), 1.63 (bs, 1H), 1.07 (s, 1H).

Step 3: 2- [4- (5-Bromo-pyrimidin-2-yl)-[1,4] diazepan-1-ylmethyl] -2-methyl-6-nitro-2,3-dihydro-imidazo [2, 1-b] oxazole. 1- (2-Bromo-4-nitro-imidazol-1-yl) -3- [4- (5-bromo-pyrimidin-2-yl)-[1,4] diazepan-1- in DMF (4 ml) IL] -2-methyl-propan-2-ol (600 mg, 1.15 mmol) was treated with NaH (33 mg, 1.4 mmol) at 0 ° C. and heated to 60 ° C. for 2 hours. The reaction mixture was cooled, diluted with saturated NH ₄ Cl (aq) and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by column chromatography to give the title compound (384 mg, 75%). ESI MS m / z 439 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 (s, 2H), 7.4 (s, 1H) 4.15 (d, J = 23 Hz, 1H) 3.81 (m, 5H), 3.06 (d, J = 38 Hz, 1H), 2.95 (m, 2H), 2.85 (m, 1H), 2.75 (m, 1H), 2.62 (d, J = 29 Hz, 1H), 1.63 (m, 2H), 1.54 (s, 3H).

Step 4: 5- (tert-Butyl-dimethyl-silanyloxymethyl) -3- (3-fluoro-4- {2- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [ 2,1-b] oxazol-2-ylmethyl)-[1,4] diazepan-1-yl] -pyrimidin-5-yl} -phenyl) -oxazolidine-2-one. 2-Nitro-6 (S)-[4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl in DMF / H2O (10 / 1.5.5 mL) ) -Benzyloxy] -6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine (160 mg, 0.40 mmol), N- [3- (3,5-difluoro-4- Iodo-phenyl) -2-oxo-oxazolidine-5 (S) -ylmethyl] -acetamide (158 mg, 0.40 mmol) (prepared as described by Das et al., WO 2006/038100 A1), Pd (Ph ₃ P ) ₄ (58 mg, 0.05 mmol) and a suspension of K ₂ CO ₃ (121 mg, 0.88 mmol) were degassed. The mixture was heated to 80 ° C. for 2.5 hours, diluted with EtOAc, washed with brine and concentrated in vacuo to give the crude product. (172 mg, 79%). ESI MS m / z 683 (M + H ^< + ^> ).

Step 5: 3- (3-Fluoro-4- {2- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl)-[1 , 4] diazepan-1-yl] -pyrimidin-5-yl} -phenyl) -5-hydroxymethyl-oxazolidin-2-one. 5- (tert-Butyl-dimethyl-silanyloxymethyl) -3- (3-fluoro-4- {2- [4- (2-methyl-6-nitro-2,3) in THF (8.0 mL). -Dihydro-imidazo [2,1-b] oxazol-2-ylmethyl)-[1,4] diazepan-1-yl] -pyrimidin-5-yl} -phenyl) -oxazolidine-2-one (580 mg,. To a solution of 84 mmol) TBAF (3.3 mL, 3.3 mmol, 1.0 M in THF) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na ₂ SO ₄ and purified by flash chromatography to give the title product (100 mg, 21%) as a yellow solid. ESI MS m / z 569 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 7.60 (dd, J = 30, 3.0 Hz, 1H), 7.36 (T, J = 20 Hz, 1H), 7.29 (d, J = 3.0 Hz, 1H), 7.25 (s, 2H), 4.70 (m, 1H), 4.10 (d, J = 25.0 Hz, 1 H), 3.95 to 4.06 (m, 2 H), 3.82 to 3.88 (m, 2 H), 3.76 (d, J = 23.0 Hz, 1 H), 3 .64 (dd, J = 33, 10.0 Hz, 1H), 3.41-3.58 (m, 2H), 3.31 (bs, 3H), 3.02 (d, J = 38.0, 1H), 2.94 (q, J = 16.0 Hz, 1H), 2.82 to 2.84 (m, 1H), 2.70 to 2.78 (m, 1H), 2.60 ( d, J = 38.0, 1H), 1.64 to 1.72 (m, 1H), 1.50 to 1.58 (m, 1H), 1.48 (s, 3H).
Example 89

  3- (3-Fluoro-4- {6- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl)-[1,4] Diazepan-1-yl] -pyridin-3-yl} -phenyl) -5-hydroxymethyl-oxazolidine-2-one:

Step 1: 1- (5-Bromo-pyridin-2-yl)-[1,4] diazepane. A solution of 5-bromo-2-fluoro-pyridine (2.0 g, 11.4 mmol), [1,4] diazepane (2.2 g, 22.8 mmol) in CH ₃ CN (5.0 mL) at 50 ° C. Stir for 3 hours. The solid and bank filter was brine and concentrated under vacuum to give the title product (1.47 g, 51%) as a brown solid. ESI MS m / z 256 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12 (d, J = 7.0 Hz, 1H), 7.45 (dd, J = 22.0, 6 Hz, 1H), 6.38 (d, J = 22.0 Hz, 1H), 3.66 (m, 4H), 2.81 (t, J = 15.0 Hz, 2H), 1.86 (m, 2H) .

Step 2: 1- (2-Bromo-4-nitro-imidazol-1-yl) -3- [4- (5-bromo-pyridin-2-yl)-[1,4] diazepan-1-yl]- 2-Methyl-propan-2-ol. The title compound uses 1- (5-bromo-pyridin-2-yl)-[1,4] diazepan instead of 1- (5-bromo-pyrimidin-2-yl)-[1,4] diazepane. Prepared by following the same procedure as described for the preparation of Example 1, Step 2. ESI MS m / z 518 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, J = 7.0 Hz, 1H), 8.01 (s, 1H), 7.48 (dd , J = 25.0, 5.0 Hz, 1H), 6.41 (d, J = 22.0 Hz, 1H), 3.89 (q, J = 35.0 Hz, 2H), 3.68-3. 74 (m, 2H), 3.60 (t, J = 16.0 Hz, 2H), 2.95 (m, 2H), 2.78 (m, 2H), 2.61 (d, J = 35. 0 Hz, 2H), 2.45 (d, J = 35.0 Hz, 2H), 2.20 (s, 1H), 1.89 (m, 2H), 1.03 (s, 3H).

Step 3: 2- [4- (5-Bromo-pyrimidin-2-yl)-[1,4] diazepan-1-ylmethyl] -2-methyl-6-nitro-2,3-dihydro-imidazo [2, 1-b] oxazole. The title compound is 1- (2-bromo-4-nitro-imidazol-1-yl) -3- [4- (5-bromo-pyridin-2-yl)-[1,4] diazepan-1-yl] 2-Methyl-propan-2-ol was converted to 1- (2-bromo-4-nitro-imidazol-1-yl) -3- [4- (5-bromo-pyrimidin-2-yl)-[1,4 Prepared by following the same procedure as described for the preparation of Example 88, Step 3, substituting for diazepan-1-yl] -2-methyl-propan-2-ol. ESI MS m / z 518 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (d, J = 7.0 Hz, 1H), 7.99 (s, 1H), 7.41 (dd , J = 16.0, 6.0 Hz, 1H), 6.41 (d, J = 23.0 Hz, 1H), 4.05 (d, J = 25.0 Hz, 1H), 3.3.74- 3.79 (m, 2H), 3.52 to 3.57 (m, 1H), 3.33 to 3.39 (m, 2H), 3.02 (d, J = 39.0 Hz, 1H), 2.90 to 2.95 (m, 4H), 2.81 to 2.87 (m, 2H), 2.72 to 2.75 (m, 1H), 2.59 (d, J = 38.0 Hz) , 1H), 1.57 (m, 1H), 1.50 (s, 3H).

Step 4: 5- (tert-Butyl-dimethyl-silanyloxymethyl) -3- (3-fluoro-4- {2- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [ 2,1-b] oxazol-2-ylmethyl)-[1,4] diazepan-1-yl] -pyrimidin-5-yl} -phenyl) -oxazolidine-2-one. The title compound is 3- (3-fluoro-4- {6- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl)-[ 1,4] diazepan-1-yl] -pyridin-3-yl} -phenyl) -5-hydroxymethyl-oxazolidin-2-one to 2- [4- (5-bromo-pyrimidin-2-yl)-[ 1,4] diazepan-1-ylmethyl] -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] was used in place of Example 88, preparation of step 4 described. Prepared by following the same procedure as ESI MS m / z 682 (M + H ^< + ^> ).

Step 5: 3- (3-Fluoro-4- {2- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl)-[1 , 4] diazepan-1-yl] -pyrimidin-5-yl} -phenyl) -5-hydroxymethyl-oxazolidin-2-one. The title compound was prepared by following the same procedure as described for the preparation of Example 88, Step 4, 5- (tert-butyl-dimethyl-silanyloxymethyl) -3- (3-fluoro-4- { 2- [4- (2-Methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl)-[1,4] diazepan-1-yl] -pyrimidine-5 -Yl} -phenyl) -oxazolidine-2-one. ESI MS m / z 569 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.21 (s, 1H), 7.60 (dd, J = 30, 3.0 Hz, 1H), 7.47 (M, 1H), 7.41 (d, J = 18.0 Hz, 1H), 7.33 (d, J = 16.0 Hz, 2H), 7.15 (s, 1H), 4.70 (m , 1H), 6.35 (d, J = 21.0 Hz, 1H), 5.23 (d, J = 2.0 Hz, 2H), 4.7 (bs, 2H), 3.84 to 3.97. (M, 6H), 3.58 to 3.97 (m, 6H), 3.33 (m, 2H), 2.97 to 3.01 (m, 2H), 2.81 to 2.91 (m , 2H), 2.69 (t, J = 27.0, 1H), 2.53 (d, J = 38.0, 1H), 1.60 (m, 2H), 1.43-1.48. (M, 4 H), 1.18 (m, 4H), 0.76 to 0.82 (m, 1H).
Example 90

  N- [3- (3-Fluoro-4- {6- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl)-[1 , 4] diazepan-1-yl] -pyridin-3-yl} -phenyl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide:

The title compound is 5- (tert-butyl-dimethyl-silanyloxymethyl) -3- (3-fluoro-4- {2- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl)-[1,4] diazepan-1-yl] -pyrimidin-5-yl} -phenyl) -oxazolidine-2-one was replaced by N- {3- [3- Performed instead of fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -2-oxo-oxazolidine-5-ylmethyl} acetamide Prepared by following the same procedure as described for the preparation of Example 88, Step 5. ESI MS m / z 609 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (s, 1H), 7.56 (m, 2H), 7.47 (m, 2H), 7. 22 (m, 2H), 6.42 (d, J = 23.0 Hz, 1H), 4.81 (m, 1H), 4.08 (t, J = 25.0 Hz, 1H), 4.02 ( d, J = 24.0 Hz, 1H), 3.91 to 3.96 (m, 1H), 3.81 (m, 1H), 3.62 to 3.74 (m, 2H), 3.36 to 3.45 (m, 2H), 3.06 (d, J = 38.0 Hz, 1H), 2.87-2.98 (m, 2H), 2.73-2.79 (m, 1H), 2.60 (d, J = 38.0, 1H), 2.03 (s, 3H), 1.67 (s, 3H), 1.50 (s, 3H), 0.82 to 0.89 ( m, 2H) .
Example 91

  3- {3-Fluoro-4- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -piperazin-1-yl] -phenyl } -5-hydroxymethyl-oxazolidine-2-one:

Step 1.3- (4- {4- [3- (2-Bromo-4-nitro-imidazol-1-yl) -2-hydroxy-2-methyl-propyl] -piperazin-1-yl} -3- Fluoro-phenyl) -5-hydroxymethyl-oxazolidine-2-one. The title compound is 3- (3-fluoro-4-piperazin-1-yl-phenyl) -5-hydroxymethyl-oxazolidine-2-one as 1- (5-bromo-pyrimidin-2-yl)-[1, 4] Prepared by following the same procedure as described for the preparation of Example 88, Step 2, substituting for diazepan. ESI MS m / z 558 (M + H ^< + ^> ). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.24 (s, 1 H), 7.45 (dd, J = 37.0, 6 Hz, 1 H), 7.12 (dd, J = 22.0, 6 Hz) , 1H), 6.98 (t, J = 24.0 Hz, 1H), 4.73 (m, 1H), 4.24 (d, J = 36.0 Hz, 1H), 4.08 (m, 4H) ), 3.86 (m, 2H), 3.69 (dd, J = 31.0, 9.0 Hz, 2H), 3.39 (bs, 2H), 3.34 (s, 2H), 3. 01 (bs, 2H), 2.83 (m, 2H), 2.69 (m, 2H), 1.13 (s, 3H).

Step 2: 3- {3-Fluoro-4- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -piperazin-1-yl ] -Phenyl} -5-hydroxymethyl-oxazolidine-2-one. The title compound is 3- (4- {4- [3- (2-bromo-4-nitro-imidazol-1-yl) -2-hydroxy-2-methyl-propyl] -piperazin-1-yl} -3. 1- (2-bromo-4-nitro-imidazol-1-yl) -3- [4- (5-bromo-pyrimidin-2-yl) -fluoro-phenyl) -5-hydroxymethyl-oxazolidine-2-one )-[1,4] diazepan-1-yl] -2-methyl-propan-2-ol, prepared by following the same procedure as described for the preparation of Example 1, Step 3. . ESI MS m / z 477 (M + H ⁺ ); ¹ H NMR (400 MHz, CD ₃ OD) δ 7.90 (s, 1H), 7.36 (m, 1H), 7.00 (m, 1H), 6 .85 (m, 1H), 4.64 (m, 1H), 3.77 to 3.94 (m, 3H), 3.63 (m, 2H), 2.87 to 3.01 (m, 3H) ), 2.78-2.86 (m, 4H), 2.83 (m, 2H), 2.69 (m, 2H), 1.6 (s, 1H), 1.18 (s, 3H) .
Example 92

  N- [3- (3-Fluoro-4- {2- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -piperazine- 1-yl] -thiazol-5-yl} -phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide:

Step 1.1- (5-Bromo-thiazol-2-yl) -piperazine. A solution of 2,5-dibromo-thiazole (1.0 g, 4.1 mmol), piperazine (0.71 g, 8.2 mmol) in BuOH (5.0 mL) was stirred at 117 ° C. for 3 hours. The solvent was removed and extracted with 30% IPA in DCM, dried over sodium sulfate and concentrated under vacuum to give the title product (1.1 g, 85%) as a brown solid. ESI MS m / z 247 (M + H ^< + ^> ).

Step 2: 1- (2-Bromo-4-nitro-imidazol-1-yl) -3- [4- (5-bromo-thiazol-2-yl) -piperazin-1-yl] -2-methyl-propane -2-ol. The title compound was prepared in Example 88 using 1- (5-bromo-pyridin-2-yl)-[1,4] diazepan in place of 1- (5-bromo-thiazol-2-yl) -piperazine. Prepared by following the same procedure as described for the preparation of Step 2. ESI MS m / z 510 (M + H ^< + ^> ).

Step 3: 2- [4- (5-Bromo-thiazol-2-yl) -piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole . The title compound is 1- (2-bromo-4-nitro-imidazol-1-yl) -3- [4- (5-bromo-thiazol-2-yl) -piperazin-1-yl] -2-methyl- Propan-2-ol was converted to 1- (2-bromo-4-nitro-imidazol-1-yl) -3- [4- (5-bromo-pyrimidin-2-yl)-[1,4] diazepan-1- Prepared by following the same procedure as described for the preparation of Example 88, step 3, substituting for [yl] -2-methyl-propan-2-ol. ESI MS m / z 430 (M + H ^< + ^> ). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.74 (s, 1H), 6.97 (s, 1H), 4.31 (d, J = 25 Hz, 2H), 4.02 (d, J = 25 Hz) , 2H), 3.30 (m, 2H), 3.24 (m, 2H), 2.78 (m, 2H), 2.67 (m, 2H), 1.60 (s, 3H).

Step 4. N- [3- (3-Fluoro-4- {2- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -piperazine- 1-yl] -thiazol-5-yl} -phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide. The title compound is 2- [4- (5-bromo-thiazol-2-yl) -piperazin-1-ylmethyl] -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] Oxazole was converted to 2- [4- (5-bromo-pyrimidin-2-yl)-[1,4] diazepan-1-ylmethyl] -2-methyl-6-nitro-2,3-dihydro-imidazo [2,1 -B] Prepared by following the same procedure as described for the preparation of Example 88, Step 5, instead of oxazole. ESI MS m / z (M + H ^< + ^> ). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (s, 1H), 7.46 (dd, J = 33.0, 5.0 Hz, 1H), 7.36 (t, J = 21.0 Hz, 1H), 7.16 (dd, J = 21.0, 5.0 Hz, 1H), 4.73 (m, 1H), 4.06 (t, J = 26 Hz, 1H), 3.99 (d, J = 26 Hz, 1H), 3.93 (bs, 2H), 3.76 (m, 1H), 3.54 (m, 2H), 3.34 (t, J = 11.0 Hz, 2H), 3 .30 (bs, 2H), 2.90 (d, J = 38.0 Hz, 1H), 2.78 (m, 2H), 2.68 (m, 4H), 1.95 (s, 3H), 1.60 (s, 3H).
Example 93
Biological activity

  Representative examples of compounds of the present invention and their reference standards (linezolid and PA-824) were assayed for antibacterial activity as follows. The minimum inhibitory concentration (MIC) for S. aureus ATCC 29213 and its isogenic strain showing resistance to linezolid was determined by the microbroth dilution method according to the NCCLS guidelines (clinical laboratory standards committee). The minimum inhibitory concentration (MIC) for Mycobacterium tuberculosis H37Rv and its resistant strains showing PA-824 resistance was determined by the method reported by Gruppo (Gruppo V., 2006). The anaerobic activity of the compounds against M. tuberculosis H37Rv was determined under Wayne conditions by the method reported by Lenaerts (Lenaerts, 2005). Results are reported as% survival at a concentration of 10 mig / mL. The antibacterial activity of exemplary compounds of the present invention and reference compounds is shown in Table 1.

  The compounds of the present invention exhibit excellent activity against gram positive species, such as S. aureus ATCC 29213. For example, a diverse set of examples with different linkers “L”, such as Example 8 and Example 31, are more potent than linezolid, especially against strains resistant to linezolid, which is 64 mcg / mL. MICs are shown, double hybrids show MICs of 8 and 4 micg / mL, respectively. All examples show excellent activity against M. tuberculosis H37Rv. However, unlike PA-824, the activity of the hybrid is not affected by strains resistant to PA-824. Examples 8 and 31 show MICs of 0.5 and 1 mig / mL against the PA-824 resistant strain of Mycobacterium tuberculosis H37Rv, respectively, while PA-824 loses its activity. The unique characteristics of the compounds of the invention that show activity against resistant strains are not expected from either class of oxazolidinones or bicyclic nitroimidazoles. Also, Example 50 is 2 times weaker than linezolid and 8 times weaker than PA-824 for in vitro MIC against aerobically grown M. tuberculosis H37Rv, but Example 50 (1 at the end of treatment) .8% bacterial viability) is greater than either linezolid (28.2% viability) or PA-824 (3.6% viability) for tuberculosis H37Rv grown anaerobically Note also that the activity is high. This is also not anticipated from either the oxazolidinone or bicyclic nitroimidazole compound classes.

  The compounds of the present invention are active against both aerobic and anaerobic bacteria and are therefore useful as a broad range of antibacterial agents. The compounds of the present invention surprisingly have a staphylococcal genus such as Staphylococcus aureus; enterococcus genus such as Fecalis; streptococcus such as pneumococci; mycobacteria even when compared to any parent class compound. Effective against several human and veterinary aerobic and anaerobic gram-positive, gram-negative pathogens, including the genus Umbrella, such as Mycobacterium tuberculosis; Helicobacter, such as H. pylori; It is. Oxazolidinones substituted with bicyclic nitroimidazoles of the present invention are used as effective drugs against C. difficile associated with tuberculosis, diarrhea or pseudomembranous colitis (PMC) including drug resistant mutants or MDRTB. obtain. The compounds of the invention are also envisioned as cytotoxic anticancer, antifungal, and antiprotozoal agents (eg, against Shigella amoeba and Neglaria sps).

  It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Cited References The following US patent documents and publications are incorporated herein by reference:

US Patent Literature US Patent No. 4,801,600 US Patent No. 4,921,869 US Patent No. 5,547,950 US Patent No. 5,736,545 US Patent No. 5,880,118 US Patent No. 5,981,528 US Pat. No. 6,087,358 US Pat. No. 6,968,962 US Pat. No. 7,129,259 US Patent Publication No. US2007 / 0155714

Other Patent Documents EPA 0316594
EPA0352781
WO2004 / 078753
WO2005 / 042542 A1
WO2005 / 054234
WO2006 / 022794
WO2006 / 038100
WO2006 / 043121

Publications Ashtekar, D.C. In addition, "In Vitro and In Vivo Activities of the Nitroimidazole CGI 17341, Ainst Mimbibium (in Vitro and In vivo Activities of 19), and the Nitromidoazole CGI 17341 .
Brickner et al. Med. Chem. 1996, 39, 673-679.
Gruppo, V.M. Other: Antimicrob. Agents Chemother. 2006, Volume 50, 1245.
Lenaerts A.L. Other: Antimicrob. Agents Chemother. 2005, 49, 2294
Nagarajan, K .; Et al., "Nitroimidazoles XXI.2,3-dihydro-6-nitroimidazo [2.1-b] oxazole with antituberculosis activity (Nitroimidazoles XXI.2,3-dihydro-6-nitroimidazo [2.1-b] oxazoles with antibiotic activity), Eur. J. et al. Med. Chem. 24: 631-633 (1989).
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Claims (15)

Compound of structural formula (I) having nitroimidazole ring, or pharmaceutically acceptable salt thereof

[Where:
R ₁ is hydrogen, (C ₁ -C ₆ ) alkyl, aryl, heteroaryl, or heterocycloalkyl;
n is 0, 1, or 2;
X ₁ and X ₂ are independently H, CF ₃ , Cl, OCF ₃ or F;
G is —OH, substituted or unsubstituted triazole, heteroaryl or —NHCOR ₂ ;
R ₂ is (C ₁ -C ₆ ) alkyl, cycloalkyl, aryl, or heteroaryl;
L is a linker or linker group selected from one or any combination of 2 to 5 of the following groups:
1) (C ₁ -C ₆ ) alkylene,
_{2) (C} 3 ~C ₈₎ cycloalkylene,
3) Arylene,
4) Heteroarylene,
5) heterocycloalkylene containing 1 to 3 heteroatoms,
6) -C (= O)-,
7) -O-,
8) -S (O) _n- , wherein n is a number of 0, 1, or 2.
_{9) -N (R 3) -} ,
_{10) -C (R 4) =} C (R 5) -,
[Wherein the carbon or nitrogen atom of the linker group is unsubstituted or substituted with 1 to 3 substituents;
R ₃ is hydrogen, (C ₁ -C ₆ ) alkyl, aryl, heteroaryl, or heterocycloalkyl;
R ₄ and R ₅ are hydrogen, (C ₁ -C ₆ ) alkyl, aryl, heteroaryl, or heterocycloalkyl, or R ₄ and R ₅ can be joined together to form a bond. it can]]. The compound according to claim 1, wherein L is a bond or a group selected from one or a combination of 2 to 3 structural elements selected from the group consisting of:

Wherein R ₁₀ , R ₁₁ , R ₁₂ are H and are unsubstituted or substituted hydroxyl, amino, alkyl, alkylamino, alkoxy, aryl, or heteroaryl, and R ₁₃ is H Yes, unsubstituted or substituted hydroxyl, amino, alkyl, alkylamino, alkoxy, aryl, or heteroaryl, or R ₁₃ can combine with a nitroimidazole ring to form a spiro ring structure. M and n are independently 0, 1 or 2 and Z is O, S or CR ₁₄ R ₁₅ [wherein R ₁₄ and R ₁₅ are independently H, An alkyl, aryl or heteroaryl group], G is —OH, substituted or unsubstituted triazole, heteroaryl, —O-hetero; Reel, or -NHCOR _2]. Spiro ring structure

The compound of claim 2, wherein A compound of structural formula (II), or a pharmaceutically acceptable salt thereof

Wherein A _{1 to} A ₆ are each independently selected from the group consisting of a bond, a heteroatom, an unsubstituted carbon, and a substituted carbon, and L ₁ and L ₂ are independently Join,

And G is —OH, substituted or unsubstituted triazole, or —NHCOCH ₃ ]. L ₂ is a bond, compounds of claim 4.   A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of claim 1 in combination with a pharmaceutically acceptable carrier.   A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of claim 2 in combination with a pharmaceutically acceptable carrier.   A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of claim 4 in combination with a pharmaceutically acceptable carrier.   A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of claim 6 in combination with a pharmaceutically acceptable carrier.   8. A method of treating a bacterial infection in a subject in need of such treatment comprising administering to the subject a pharmaceutical composition according to claim 7.   9. A method of treating a bacterial infection in a subject in need of such treatment comprising administering to the subject a pharmaceutical composition according to claim 8.   10. A method of treating a bacterial infection in a subject in need of such treatment comprising administering to the subject a pharmaceutical composition according to claim 9.   11. A method of treating a bacterial infection in a subject in need of such treatment comprising administering to the subject a pharmaceutical composition according to claim 10. (A) (S, S) -N- {3- [3-Fluoro-4- (4- {2- [4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b ] [1,3] oxazin-6-yloxymethyl) -phenoxy] -acetyl} -piperazin-1-yl) -phenyl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide;
(B) (S, S) -N- (3- {3-Fluoro-4- [4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxymethyl) -benzyloxy] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(C) (S, S) -N- (3- {3-Fluoro-4- [3- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxymethyl) -benzyloxy] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(D) (S, S) -N- (3- {3-Fluoro-4- [5- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxymethyl) -pyridin-2-yloxy] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(E) (S, S) -N- (3- {3-Fluoro-4- [4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxymethyl) -phenoxy] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(F) (S, S) -N- [3- (3-Fluoro-4- {1- [4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1 , 3] oxazin-6-yloxymethyl) -benzyl] -1H- [1,2,3] triazol-4-ylmethoxy} -phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide;
(G) (S, S) -N- (3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxy) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(H) (S, S) -N- (3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxy) -pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(I) (S, S) -N- (3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxy) -pyridin-4-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(J) N- (3- {3-Fluoro-4- [5- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -pyridine- 3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(K) (S, S) -N- (3- {3-Fluoro-4- [5- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxymethyl) -pyridin-2-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(L) (S, S) -N- (3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxymethyl) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(M) (S, S) -N- (3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxy) -pyridazin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(N) (S, S) -N- (3- {3-Fluoro-4- [4-morpholin-4-yl-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1 -B] [1,3] oxazin-6-yloxy) -pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(O) (S, S) -N- (3- {3-Fluoro-4- [4-methoxy-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [ 1,3] oxazin-6-yloxy) -pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(P) (S, S) -N- (3- {4- [4-dimethylamino-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 ] Oxazin-6-yloxy) -pyrimidin-5-yl] -3-fluoro-phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(Q) (S, S) -5- {4- [5- (acetylamino-methyl) -2-oxo-oxazolidine-3-yl] -2-fluoro-phenyl} -2- (2-nitro-6) , 7-Dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -nicotinic acid methyl ester;
(R) (S, S) -5- {4- [5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenyl} -2- (2-nitro-6) , 7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -nicotinic acid;
(S) (S, S) -N- (3- {3-Fluoro-4- [4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxy) -pyrimidin-2-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(T) (S, S) -N- (3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxy) -pyrimidin-4-yl] -phenyl} -2-oxo-oxazolidin-5-ylmethyl) -acetamide;
(U) (S, S) -N- (3- {3-Fluoro-4- [5-methyl-6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [ 1,3] oxazin-6-yloxy) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(V) (S, S) -N- (3- {3-Fluoro-4- [2-methyl-6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [ 1,3] oxazin-6-yloxy) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(W) N- (3- {3-Fluoro-4- [5- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -pyridine- 2-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(X) (S, S) -N- (3- {3-fluoro-4- [4- (4-methoxy-benzyloxy) -2- (2-nitro-6,7-dihydro-5H-imidazo [ 2,1-b] [1,3] oxazin-6-yloxy) -pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(Y) (S, S) -N- (3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxy) -6-oxo-1,6-dihydro-pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(Z) (S, S) -N- (3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxy) -4-trifluoromethyl-pyrimidin-5-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(Aa) (S, S) -N- {3- [2,6-difluoro-4 ′-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxymethyl) -biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide;
(Bb) N- {3- [4- (6-Nitro-imidazo [2,1-b] -2 (3H) -8-aza-spiro [4.5] des-8-yl) -3-fluoro Phenyl] -2-oxo-oxazolidine-5 (S) -ylmethyl} -acetamide;
(Cc) (S, R) -3- [2-Fluoro-4 '-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yl Oxymethyl) -biphenyl-4-yl] -5-hydroxymethyl-oxazolidine-2-one;
(Dd) (S, S) -3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxy) -pyrimidin-5-yl] -phenyl} -5-hydroxymethyl-oxazolidin-2-one;
(Ee) (S, R) -3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxy) -pyridin-3-yl] -phenyl} -5-hydroxymethyl-oxazolidine-2-one;
(Ff) (S, S) -N- {3- [2-Fluoro-4 '-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine- 6-yloxymethyl) -biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide;
(Gg) (S, S) -N- [3- (3-Fluoro-4- {4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1 , 3] oxazin-6-yloxy) -acetyl] -piperazin-1-yl} -phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide;
(Hh) N- (3- {3-Fluoro-4- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -piperazine- 1-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(Ii) (S, R) -3- [2-Fluoro-4 '-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yl Oxymethyl) -biphen-4-yl] -5- [1,2,3] triazol-1-ylmethyl-oxazolidine-2-one;
(Jj) (S, R) -3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 -Yloxymethyl) -pyridin-3-yl] -phenyl} -5- [1,2,3] triazol-1-ylmethyl-oxazolidine-2-one;
(Kk) N- {3- [2-Fluoro-4 '-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -biphenyl-4- Yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide;
(Ll) N- {3- [2-Fluoro-3 '-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -biphenyl-4- Yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide;
(Mm) N- {3- [2'-Chloro-2-fluoro-4 '-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -Biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide;
(Nn) N- {3- [3'-Chloro-2-fluoro-4 '-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -Biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide;
(Oo) N- {3- [3'-cyano-2-fluoro-4 '-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -Biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide;
(Pp) N- (3- {2-Fluoro-4 '-[(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -amino]- Biphenyl-4-yl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(Qq) (S, S) -N- (3- {3-Fluoro-4- [3- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxy) -propenyl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(Rr) (E) -N- (3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine- 6 (S) -yloxy) -vinyl] -phenyl} -2-oxo-oxazolidine-5 (S) -ylmethyl) -acetamide;
(Ss) N- (3- {3-Fluoro-4- [1- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 (S) -Yloxymethyl) -vinyl] -phenyl} -2-oxo-oxazolidine-5 (S) -ylmethyl) -acetamide;
(Tt) N- (3- {3-Fluoro-4- [2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -Acetyl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(Uu) N- (3- {3-Fluoro-4- [1-hydroxy-1-hydroxymethyl-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1 , 3] oxazin-6-yloxy) -ethyl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(Vv) (S, S) -N- (3- {3-Fluoro-4- [3- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] Oxazin-6-yloxy) -prop-1-ynyl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(Ww) (S, S) -N- {3- [2,2′-difluoro-5 ′-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3 ] Oxazin-6-yloxymethyl) -biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide;
(Xx) (S, S) -N- {3- [2-Fluoro-3 '-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine- 6-loxymethyl) -biphenyl-4-yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide;
(Yy) N- {3- [3-Fluoro-4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethoxy) -phenyl] -2- Oxo-oxazolidine-5-ylmethyl} -acetamide; and (zz) N-(((5S) -3- (3-fluoro-4- (2-((2-methyl-6-nitro-2,3-dihydro A compound selected from the group consisting of imidazo [2,1-b] oxazol-2-yl) methoxy) pyrimidin-5-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide, and pharmaceuticals thereof Acceptable salt. (A) N-(((S) -3- (3-Fluoro-4- (5-(((S) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [ 1,3] -oxazin-6-yloxy) methyl) pyridin-3-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide;
(B) N-(((S) -3- (3-Fluoro-4- (2-(((S) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [ 1,3] -oxazin-6-yloxy) methyl) pyridin-4-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide;
(C) N-(((S) -3- (3-Fluoro-4- (4-(((S) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [ 1,3] -oxazin-6-yloxy) methyl) pyridin-2-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide;
(D) N-(((S) -3- (3-Fluoro-4- (6-(((S) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [ 1,3] -oxazin-6-yloxy) methyl) pyridin-2-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide;
(E) N-(((S) -3- (3-Fluoro-4- (6-(((S) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [ 1,3] -oxazin-6-yloxy) methyl) pyridazin-3-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide;
(F) N-(((S) -3- (3-Fluoro-4- (5-(((S) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [ 1,3] -oxazin-6-yloxy) methyl) pyrazin-2-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide;
(G) N-({(5S) -3- [3-Fluoro-4- (2- {4-[(2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] [ 1,3] oxazol-2-yl) methyl] -1-piperazinyl} -5-pyrimidinyl) phenyl] -2-oxo-1,3-oxazolidine-5-yl} methyl) acetamide;
(H) (S, S) -N- (3- {2,3′-difluoro-4 ′-{-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1, 3] oxazin-6-yloxymethyl) -biphenyl-4-yl] -2-oxo-oxazolidine-5-yl} methyl) acetamide;
(I) N-[((5S) -3- {3-Fluoro-4- [5-({[(6S) -2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yl] oxy} methyl) -2-thienyl] phenyl} -2-oxo-1,3-oxazolidine-5-yl) methyl] acetamide;
(J) N-({(5S) -3- [3-Fluoro-4- (6- {4-[(2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b] [ 1,3] oxazol-2-yl) methyl] -1-piperazinyl} -3-pyridinyl) phenyl] -2-oxo-1,3-oxazolidine-5-yl} methyl) acetamide;
(K) 3- {3-Fluoro-4- [5- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl)- Pyridin-2-yl] -phenyl} -5-hydroxymethyl-oxazolidine-2-one;
(L) 3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyridazine- 3-yl] -phenyl} -5-hydroxymethyl-oxazolidine-2-one;
(M) 3- {3-Fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl)- Pyridin-3-yl] -phenyl} -5-hydroxymethyl-oxazolidin-2-one;
(N) N- (3- {3,5-difluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6 Yloxy) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(O) 3- {3-Fluoro-4- [2-methyl-6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy ) -Pyridin-3-yl] -phenyl} -5-hydroxymethyl-oxazolidin-2-one;
(P) 3- {3,5-difluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy)- Pyridin-3-yl] -phenyl} -5-hydroxymethyl-oxazolidin-2-one;
(Q) 5-hydroxymethyl-3- {4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyridine -3-yl] -3-trifluoromethoxy-phenyl} -oxazolidine-2-one;
(R) 5-hydroxymethyl-3- [6 '-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy)-[2, 3 ′] bipyridinyl-5-yl] -oxazolidine-2-one;
(S) 3- {4- [4-Dimethylamino-2- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxy) -pyrimidine -5-yl] -3-fluoro-phenyl} -5-hydroxymethyl-oxazolidine-2-one;
(T) N- [3- (3-Fluoro-4- {5-[(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-ylamino) ) -Methyl] -pyridin-2-yl} -phenyl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide;
(U) N- [3- (3-Fluoro-4- {6-[(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-ylamino) ) -Methyl] -pyridin-3-yl} -phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide;
(V) 5-hydroxymethyl-3- {4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yloxymethyl) -Pyridin-3-yl] -3-trifluoromethoxy-phenyl} -oxazolidine-2-one;
(W) 3- [2-Fluoro-4 '-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -biphenyl-4-yl]- 5-hydroxymethyl-oxazolidine-2-one;
(X) N- {3- [2-fluoro-4 '-(2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -biphenyl-4- Yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide;
(Y) N- (3- {3-Fluoro-4- [6- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -pyridine- 3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(Z) N- [3- (3-Fluoro-4- {2- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -Piperazin-1-yl] -pyrimidin-5-yl} -phenyl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide;
(Aa) 3- (3-Fluoro-4- {2- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -piperazine- 1-yl] -pyrimidin-5-yl} -phenyl) -5-hydroxymethyl-oxazolidine-2-one;
(Bb) 3- {3-Fluoro-4- [6- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -pyridin-3-yl ] -Phenyl} -5-hydroxymethyl-oxazolidine-2-one;
(Cc) N- (3- {2-Fluoro-4 '-[4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -piperazine -1-yl] -biphenyl-4-yl} -2-oxo-oxazolidine-5-ylmethyl) -acetamide;
(Dd) N- [3- (3-Fluoro-4- {6- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -Piperazin-1-yl] -pyridin-3-yl} -phenyl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide;
(Ee) Mono- (3- {3-fluoro-4- [6- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-phosphate) Yloxy) -pyridin-3-yl] -phenyl} -2-oxo-oxazolidine-5-ylmethyl) ester;
(Ff) 3- [3-Fluoro-4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yl) -phenyl] -5 Hydroxymethyl-oxazolidin-2-one;
(Gg) N- {3- [3-Fluoro-4- (2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazin-6-yl) -phenyl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide;
(Hh) 2-allyl-2- (4-bromo-phenyl) -6-nitro-2,3-dihydro-imidazo [2,1-b] oxazole;
(Ii) N- {3- [4 '-(2-allyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -2-fluoro-biphenyl-4- Yl] -2-oxo-oxazolidine-5-ylmethyl} -acetamide;
(Jj) 3- [4- (2-Allyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-yl) -phenyl] -5-hydroxymethyl-oxazolidine-2- on;
(Kk) 3- (3-Fluoro-4- {2- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl)-[1 , 4] diazepan-1-yl] -pyrimidin-5-yl} -phenyl) -5-hydroxymethyl-oxazolidin-2-one;
(Ll) 3- (3-Fluoro-4- {6- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl)-[1 , 4] diazepan-1-yl] -pyridin-3-yl} -phenyl) -5-hydroxymethyl-oxazolidin-2-one;
(Mm) N- [3- (3-Fluoro-4- {6- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -[1,4] diazepan-1-yl] -pyridin-3-yl} -phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide;
(Nn) 3- {3-Fluoro-4- [4- (2-methyl-6-nitro-2,3-dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -piperazin-1-yl ] -Phenyl} -5-hydroxymethyl-oxazolidine-2-one; and (oo) N- [3- (3-fluoro-4- {2- [4- (2-methyl-6-nitro-2,3) -Dihydro-imidazo [2,1-b] oxazol-2-ylmethyl) -piperazin-1-yl] -thiazol-5-yl} -phenyl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide And a pharmaceutically acceptable salt thereof.

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